Diaminothiazoles useful as Axl inhibitors

ABSTRACT

Diaminothiazoles and pharmaceutical compositions containing them are disclosed as being useful in inhibiting the activity of the receptor protein tyrosine kinase Axl. Methods of using the diaminothiazoles in treating diseases or conditions associated with Axl activity are also disclosed.

CROSS-REFERENCE(S) TO RELATED APPLICATION(S)

This application claims the benefit under 35 U.S.C. §119(e) of U.S.Provisional Patent Application No. 60/876,963 filed Dec. 22, 2006, whichapplication is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention is directed to diaminothiazoles and pharmaceuticalcompositions thereof which are useful as inhibitors of the receptorprotein tyrosine kinase known as Axl. This invention is also directed tomethods of using the compounds and compositions in treating diseases andconditions associated with Axl activity, particularly in treatingdiseases and conditions associated with angiogenesis and/or cellproliferation.

BACKGROUND OF THE INVENTION

All of the protein kinases that have been identified to date in thehuman genome share a highly conserved catalytic domain of around 300 aa.This domain folds into a bi-lobed structure in which reside ATP-bindingand catalytic sites. The complexity of protein kinase regulation allowsmany potential mechanisms of inhibition including competition withactivating ligands, modulation of positive and negative regulators,interference with protein dimerization, and allosteric or competitiveinhibition at the substrate or ATP binding sites.

Axl (also known as UFO, ARK, and Tyro7; nucleotide accession numbersNM_(—)021913 and NM_(—)001699; protein accession numbers NP_(—)068713and NP_(—)001690) is a receptor protein tyrosine kinase (RTK) thatcomprises a C-terminal extracellular ligand-binding domain andN-terminal cytoplasmic region containing the catalytic domain. Theextracellular domain of Axl has a unique structure that juxtaposesimmunoglobulin and fibronectin Type III repeats and is reminiscent ofthe structure of neural cell adhesion molecules. Axl and its two closerelatives, Mer/Nyk and Sky (Tyro3/Rse/Dtk), collectively known as theTyro3 family of RTK's, all bind and are stimulated to varying degrees bythe same ligand, Gas6 (growth arrest specific-6), a ˜76 kDa secretedprotein with significant homology to the coagulation cascade regulator,Protein S. In addition to binding to ligands, the Axl extracellulardomain has been shown to undergo homophilic interactions that mediatecell aggregation, suggesting that one important function of Axl may beto mediate cell-cell adhesion.

Axl is predominantly expressed in the vasculature in both endothelialcells (EC's) and vascular smooth muscle cells (VSMC's) and in cells ofthe myeloid lineage and is also detected in breast epithelial cells,chondrocytes, Sertoli cells and neurons. Several functions includingprotection from apoptosis induced by serum starvation, TNF-α or theviral protein E1A, as well as migration and cell differentiation havebeen ascribed to Axl signaling in cell culture. However, Axl−/− miceexhibit no overt developmental phenotype and the physiological functionof Axl in vivo is not clearly established in the literature.

Angiogenesis (the formation of new blood vessels) is limited tofunctions such as wound healing and the female reproductive cycle inhealthy adults. This physiological process has been co-opted by tumors,thus securing an adequate blood supply that feeds tumor growth andfacilitates metastasis. Deregulated angiogenesis also a feature of manyother diseases (for example, psoriasis, rheumatoid arthritis,endometriosis and blindness due to age-related macular degeneration(AMD), retinopathy of prematurity and diabetes) and often contributes tothe progression or pathology of the condition.

The overexpression of Axl and/or its ligand has also been reported in awide variety of solid tumor types including, but not limited to, breast,renal, endometrial, ovarian, thyroid, non-small cell lung carcinoma, anduveal melanoma as well as in myeloid leukemia's. Furthermore, itpossesses transforming activity in NIH3T3 and 32D cells. It has beendemonstrated that loss of Axl expression in tumor cells blocks thegrowth of solid human neoplasms in an in vivo MDA-MB-231 breastcarcinoma xenograft model. Taken together, these data suggest Axlsignaling can independently regulate EC angiogenesis and tumor growthand thus represents a novel target class for tumor therapeuticdevelopment.

The expression of Axl and Gas6 proteins is upregulated in a variety ofother disease states including endometriosis, vascular injury and kidneydisease and Axl signaling is functionally implicated in the latter twoindications. Axl-Gas6 signaling amplifies platelet responses and isimplicated in thrombus formation. Axl may thus potentially represent atherapeutic target for a number of diverse pathological conditionsincluding solid tumors, including, but not limited to, breast, renal,endometrial, ovarian, thyroid, non-small cell lung carcinoma and uvealmelanoma; liquid tumors, including but not limited to, leukemias(particularly myeloid leukemias) and lymphomas; endometriosis, vasculardisease/injury (including but not limited to restenosis, atherosclerosisand thrombosis), psoriasis; visual impairment due to maculardegeneration; diabetic retinopathy and retinopathy of prematurity;kidney disease (including but not limited to glomerulonephritis,diabetic nephropathy and renal transplant rejection), rheumatoidarthritis; osteoporosis, osteoarthritis and cataracts.

SUMMARY OF THE INVENTION

This invention is directed to certain diaminothiazoles which are usefulas Axl inhibitors, methods of using such derivatives in treatingdiseases and conditions associated with Axl activity and pharmaceuticalcompositions comprising such derivatives.

Accordingly, in one aspect this invention is directed to compounds offormula (I):

wherein:

-   R¹, R⁴ and R⁵ are each independently hydrogen, alkyl, aryl, aralkyl,    —C(O)R¹⁰, or —C(O)N(R⁶)R⁷;-   R² is aryl or heteroaryl, the aryl or heteroaryl being optionally    substituted with one or more substituents selected from the group    consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,    —R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,    —R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or    2), —R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,    —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,    —R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t    is 1 or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹    (where p is 0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or    2);-   R³ is heteroaryl having at least six ring atoms, the heteroaryl    being optionally substituted with one or more substituents selected    from the group consisting of cyano, nitro, halo, haloalkyl, alkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,    —R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,    —R¹⁰—OR¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2),    —R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,    —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,    —R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t    is 1 or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹    (where p is 0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or    2);-   each R⁶ and R⁷ are each independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹¹—OR⁹, —R¹¹—CN, —R¹¹—NO₂, —R¹¹—N(R⁹)₂,    —R¹¹—C(O)OR⁹ and —R¹¹—C(O)N(R⁹)₂;-   each R⁹ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted aralkenyl, optionally substituted    aralkynyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl;-   each R¹⁰ is independently selected from the group consisting of a    direct bond, an optionally substituted straight or branched alkylene    chain, an optionally substituted straight or branched alkenylene    chain and an optionally substituted straight or branched alkynylene    chain;-   each R¹¹ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain, an    optionally substituted straight or branched alkenylene chain and an    optionally substituted straight or branched alkynylene chain; and-   each R¹² is hydrogen, alkyl, cyano, nitro or —OR⁹;-   with the proviso that the compound is not    N²-(1,4-benzodioxan-6-yl)-5-(pyridin-2-yl)thiazole-2,4-diamine, and    when R² is phenyl, 4-chlorophenyl or methoxy-substituted phenyl, R³    is not quinolin-2-yl, pyridinyl or substituted pyridinyl,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

In another aspect, this invention is directed to pharmaceuticalcompositions comprising a pharmaceutically acceptable excipient and atherapeutically effective amount of a compound of formula (I), asdescribed above, as an isolated stereoisomer or mixture thereof, or apharmaceutically acceptable salt thereof.

In another aspect, this invention is directed to methods of treating adisease or condition associated with Axl activity in a mammal, whereinthe methods comprise administering to the mammal a therapeuticallyeffective amount of a compound of formula (I), as described above, as anisolated stereoisomer or mixture thereof, or a pharmaceuticallyacceptable salt thereof, or a therapeutically effective amount of apharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of formula (I), as described above, as anisolated stereoisomer or mixture thereof, or a pharmaceuticallyacceptable salt thereof.

In another aspect, this invention provides assays to determine acompound of the invention effectiveness in inhibiting Axl activity in acell-based assay.

In another aspect, the scope of the invention is not meant to includeany compounds disclosed or claimed in WO2000/075120 or in WO2001/56567.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated:

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to twelve carbon atoms, preferably one toeight carbon atoms or one to six carbon atoms, and which is attached tothe rest of the molecule by a single bond, for example, methyl, ethyl,n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.Unless stated otherwise specifically in the specification, an alkylgroup may be optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR¹⁴,—OC(O)—R¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂,—N(R¹⁴)C(O)OR¹⁴, —N(R¹⁴)C(O)R¹⁴, —N(R¹⁴)S(O)_(t)R¹⁴ (where t is 1 or 2),—S(O)_(t)OR¹⁴ (where t is 1 or 2), —S(O)_(p)R¹⁴ (where p is 0, 1 or 2),and —S(O)_(t)N(R¹⁴)₂ (where t is 1 or 2) where each R¹⁴ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl(optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl, and whereeach of the above substituents is unsubstituted unless otherwiseindicated.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, having from two to twelve carbon atoms,preferably one to eight carbon atoms and which is attached to the restof the molecule by a single bond, for example, ethenyl, prop-1-enyl,but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless statedotherwise specifically in the specification, an alkenyl group may beoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR¹⁴, —OC(O)—R¹⁴,—N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴—C(O)N(R¹⁴)₂, —N(R¹⁴)C(O)OR¹⁴,—N(R¹⁴)C(O)R¹⁴, —N(R¹⁴)S(O)_(t)R¹⁴ (where t is 1 or 2), —S(O)_(t)OR¹⁴(where t is 1 or 2), —S(O)_(p)R¹⁴ (where p is 0, 1 or 2), and—S(O)_(t)N(R¹⁴)₂ (where t is 1 or 2) where each R¹⁴ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl(optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl, and whereeach of the above substituents is unsubstituted unless otherwiseindicated.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, optionally containing at least one double bond,having from two to twelve carbon atoms, preferably one to eight carbonatoms and which is attached to the rest of the molecule by a singlebond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, andthe like. Unless stated otherwise specifically in the specification, analkynyl group may be optionally substituted by one or more of thefollowing substituents: halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR¹⁴, —OC(O)—R¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴,—C(O)N(R¹⁴)₂, —N(R¹⁴)C(O)OR¹⁴, —N(R¹⁴)C(O)R¹⁴, —N(R¹⁴)S(O)_(t)R¹⁴ (wheret is 1 or 2), —S(O)_(t)OR¹⁴ (where t is 1 or 2), —S(O)_(p)R¹⁴ (where pis 0, 1 or 2), and —S(O)_(t)N(R¹⁴)₂ (where t is 1 or 2) where each R¹⁴is independently hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl (optionally substituted with one or more halogroups), aralkyl, heterocyclyl, heterocylylalkyl, heteroaryl orheteroarylalkyl, and where each of the above substituents isunsubstituted unless otherwise indicated.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through one carbon in the alkylene chain or through any two carbonswithin the chain. Unless stated otherwise specifically in thespecification, an alkylene chain may be optionally substituted by one ormore of the following substituents: halo, cyano, nitro, aryl,cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl,—OR¹⁴, —OC(O)—R¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂,—N(R¹⁴)C(O)OR¹⁴, —N(R¹⁴)C(O)R¹⁴, —N(R¹⁴)S(O)_(t)R¹⁴ (where t is 1 or 2),—S(O)_(t)OR¹⁴ (where t is 1 or 2), —S(O)_(p)R¹⁴ (where p is 0, 1 or 2),and —S(O)_(t)N(R¹⁴)₂ (where t is 1 or 2) where each R¹⁴ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl(optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl, and whereeach of the above substituents is unsubstituted unless otherwiseindicated.

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onedouble bond and having from two to twelve carbon atoms, for example,ethenylene, propenylene, n-butenylene, and the like. The alkenylenechain is attached to the rest of the molecule through a double bond or asingle bond and to the radical group through a double bond or a singlebond. The points of attachment of the alkenylene chain to the rest ofthe molecule and to the radical group can be through one carbon or anytwo carbons within the chain. Unless stated otherwise specifically inthe specification, an alkenylene chain may be optionally substituted byone or more of the following substituents: halo, cyano, nitro, aryl,cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl,—OR¹⁴, —OC(O)—R¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴, —C(O)N(R¹⁴)₂,—N(R¹⁴)C(O)OR¹⁴, —N(R¹⁴)C(O)R¹⁴, —N(R¹⁴)S(O)_(t)R¹⁴ (where t is 1 or 2),—S(O)_(t)OR¹⁴ (where t is 1 or 2), —S(O)_(p)R¹⁴ (where p is 0, 1 or 2),and —S(O)_(t)N(R¹⁴)₂ (where t is 1 or 2) where each R¹⁴ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl(optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl, and whereeach of the above substituents is unsubstituted unless otherwiseindicated.

“Alkynylene” or “alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onetriple bond and having from two to twelve carbon atoms, for example,propynylene, n-butynylene, and the like. The alkynylene chain isattached to the rest of the molecule through a single bond and to theradical group through a double bond or a single bond. The points ofattachment of the alkynylene chain to the rest of the molecule and tothe radical group can be through one carbon or any two carbons withinthe chain. Unless stated otherwise specifically in the specification, analkynylene chain may be optionally substituted by one or more of thefollowing substituents: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro,aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo,trimethylsilanyl, —OR¹⁴, —OC(O)—R¹⁴, —N(R¹⁴)₂, —C(O)R¹⁴, —C(O)OR¹⁴,—C(O)N(R¹⁴)₂, —N(R¹⁴)C(O)OR¹⁴, —N(R¹⁴)C(O)R¹⁴, —N(R¹⁴)S(O)_(t)R¹⁴ (wheret is 1 or 2), —S(O)_(t)OR¹⁴ (where t is 1 or 2), —S(O)_(p)R¹⁴ (where pis 0, 1 or 2), and —S(O)_(t)N(R¹⁴)₂ (where t is 1 or 2) where each R¹⁴is independently hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl (optionally substituted with one or more halogroups), aralkyl, heterocyclyl, heterocylylalkyl, heteroaryl orheteroarylalkyl, and where each of the above substituents isunsubstituted unless otherwise indicated.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined above containing one to twelve carbon atoms.The alkyl part of the alkoxy radical may be optionally substituted asdefined above for an alkyl radical.

“Alkoxyalkyl” refers to a radical of the formula —R_(b)—O—R_(a) whereR_(a) is an alkyl radical as defined above and R_(b) is an alkylenechain as defined above. The oxygen atom may be bonded to any carbon inthe alkyl radical or the alkylene chain. The alkyl part of thealkoxyalkyl radical may be optionally substituted as defined above foran alkyl group and the alkylene chain part of the alkoxyalkyl radicalmay be optionally substituted as defined above for an alkylene chain.

“Aryl” refers to aromatic monocyclic or multicyclic hydrocarbon ringsystem consisting only of hydrogen and carbon and containing from six toeighteen carbon atoms, where the ring system may be partially or fullysaturated. Aryl groups include, but are not limited to, groups such asfluorenyl, phenyl and naphthyl. Unless stated otherwise specifically inthe specification, the term “aryl” or the prefix “ar-” (such as in“aralkyl”) is meant to include aryl radicals optionally substituted byone or more substituents independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,haloalkynyl, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl,optionally substituted cycloalkylalkynyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heterocyclylalkenyl, optionally substitutedheterocyclylalkynyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyl,optionally substituted heteroarylalkynyl, —R¹⁵—OR¹⁴, —R¹⁵—C(O)—R¹⁴,—R¹⁵—N(R¹⁴)₂, —R¹⁵—C(O)R¹⁴, —R¹⁵—C(O)OR¹⁴, —R¹⁵—C(O)N(R¹⁴)₂,—R¹⁵—O—R¹⁶—C(O)N(R¹⁴)₂, —R¹⁵—N(R¹⁴)C(O)OR¹⁴, —R¹⁵—N(R¹⁴)C(O)R¹⁴,—R¹⁵—N(R¹⁴)S(O)_(t)R¹⁴ (where t is 1 or 2), —R¹⁵—S(O)_(t)OR¹⁴ (where tis 1 or 2), —R¹⁵—S(O)_(p)R¹⁴ (where p is 0, 1 or 2), and—R¹⁵—S(O)_(t)N(R¹⁴)₂ (where t is 1 or 2), where each R¹⁴ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, each R¹⁵ is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R¹⁵ is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R_(b)—R_(c) where R_(b) isan alkylene chain as defined above and R_(c) is one or more arylradicals as defined above, for example, benzyl, diphenylmethyl and thelike. The alkylene chain part of the aralkyl radical may be optionallysubstituted as described above for an alkylene chain. The aryl part ofthe aralkyl radical may be optionally substituted as described above foran aryl group.

“Aralkenyl” refers to a radical of the formula —R_(d)—R_(c) where R_(d)is an alkenylene chain as defined above and R_(c) is one or more arylradicals as defined above. The aryl part of the aralkenyl radical may beoptionally substituted as described above for an aryl group. Thealkenylene chain part of the aralkenyl radical may be optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R_(e)R_(c) where R_(e)is an alkynylene chain as defined above and R_(c) is one or more arylradicals as defined above. The aryl part of the aralkynyl radical may beoptionally substituted as described above for an aryl group. Thealkynylene chain part of the aralkynyl radical may be optionallysubstituted as defined above for an alkynylene chain.

“Aryloxy” refers to a radical of the formula —OR_(c) where R_(c) is anaryl group as defined above. The aryl part of the aryloxy radical may beoptionally substituted as defined above.

“Aralkyloxy” refers to a radical of the formula —OR_(f) where R_(f) isan aralkyl group as defined above. The aralkyl part of the aralkyloxyradical may be optionally substituted as defined above.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms,and which is saturated or unsaturated and attached to the rest of themolecule by a single bond. Monocyclic radicals include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornanyl (i.e., bicyclo[2,2,1]heptanyl), norbornenyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwisestated specifically in the specification, the term “cycloalkyl” is meantto include cycloalkyl radicals which are optionally substituted by oneor more substituents independently selected from the group consisting ofalkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo,thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl,optionally substituted cycloalkylalkynyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heterocyclylalkenyl, optionally substitutedheterocyclylalkynyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyl,optionally substituted heteroarylalkynyl, —R¹⁵—OR¹⁴, —R¹⁵C(O)—R¹⁴,—R¹⁵—N(R¹⁴)₂, —R¹⁵—C(O)R¹⁴, —R¹⁵—C(O)OR¹⁴, —R¹⁵—C(O)N(R¹⁴)₂,—R¹⁵—N(R¹⁴)C(O)OR¹⁴, —R¹⁵—N(R¹⁴)C(O)R¹⁴, —R¹⁵—N(R¹⁴)S(O)_(t)R¹⁴ (where tis 1 or 2), —R¹⁵—S(O)_(t)OR¹⁴ (where t is 1 or 2), —R¹⁵—S(O)_(p)R¹⁴(where p is 0, 1 or 2), and —R¹⁵—S(O)_(t)N(R¹⁴)₂ (where t is 1 or 2),where each R¹⁴ is independently hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl, and each R¹⁵ is independently a directbond or a straight or branched alkylene or alkenylene chain, and whereeach of the above substituents is unsubstituted unless otherwiseindicated.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)R_(g) whereR_(b) is an alkylene chain as defined above and R_(g) is a cycloalkylradical as defined above. The alkylene chain and the cycloalkyl radicalmay be optionally substituted as defined above.

“Cycloalkylalkenyl” refers to a radical of the formula —R_(d)R_(g) whereR_(d) is an alkenylene chain as defined above and R_(g) is a cycloalkylradical as defined above. The alkenylene chain and the cycloalkylradical may be optionally substituted as defined above.

“Cycloalkylalkynyl” refers to a radical of the formula —R_(e)R_(g) whereR_(e) is an alkynylene radical as defined above and R_(g) is acycloalkyl radical as defined above. The alkynylene chain and thecycloalkyl radical may be optionally substituted as defined above.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, for example,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like. The alkyl part of thehaloalkyl radical may be optionally substituted as defined above for analkyl group.

“Haloalkenyl” refers to an alkenyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above. The alkenylpart of the haloalkyl radical may be optionally substituted as definedabove for an alkenyl group.

“Haloalkynyl” refers to an alkynyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above. The alkynylpart of the haloalkyl radical may be optionally substituted as definedabove for an alkynyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical that comprises one to twelve carbon atoms and from one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur. Unless stated otherwise specifically in the specification, theheterocyclyl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be partially or fullysaturated. The heterocyclyl may be attached to the rest of the moleculethrough any atom on the ring(s). Examples of such heterocyclyl radicalsinclude, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless statedotherwise specifically in the specification, the term “heterocyclyl” ismeant to include heterocyclyl radicals as defined above which areoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,—R¹⁵—OR¹⁴, —R¹⁵—OC(O)—R¹⁴, —R¹⁵—N(R¹⁴)₂, —R¹⁵—C(O)R¹⁴, —R¹⁵—C(O)OR¹⁴,—R¹⁵—C(O)N(R¹⁴)₂, —R¹⁵—N(R¹⁴)C(O)OR¹⁴, —R¹⁵—N(R¹⁴)C(O)R¹⁴,—R¹⁵—N(R¹⁴)S(O)_(t)R¹⁴ (where t is 1 or 2), —R¹⁵—S(O)_(t)OR¹⁴ (where tis 1 or 2), —R¹⁵—S(O)_(p)R¹⁴ (where p is 0, 1 or 2), and—R¹⁵—S(O)_(t)N(R¹⁴)₂ (where t is 1 or 2), where each R¹⁴ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, and each R¹⁵ is independently a direct bond or astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heterocyclyl radical to the rest of the molecule is through anitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical maybe optionally substituted as described above for heterocyclyl radicals.Examples of such N-heterocyclyl radicals include, but are not limitedto, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl,imidazolinyl, and imidazolidinyl.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)R_(h) whereR_(b) is an alkylene chain as defined above and R_(h) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkyl radical at the nitrogen atom. The alkylene chain of theheterocyclylalkyl radical may be optionally substituted as defined abovefor an alkylene chain. The heterocyclyl part of the heterocyclylalkylradical may be optionally substituted as defined above for aheterocyclyl group.

“Heterocyclylalkenyl” refers to a radical of the formula —R_(d)R_(h)where R_(d) is an alkenylene chain as defined above and R_(h) is aheterocyclyl radical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkenylene chain at the nitrogen atom. The alkenylene chain of theheterocyclylalkenyl radical may be optionally substituted as definedabove for an alkenylene chain. The heterocyclyl part of theheterocyclylalkenyl radical may be optionally substituted as definedabove for a heterocyclyl group.

“Heterocyclylalkynyl” refers to a radical of the formula —R_(e)R_(h)where R_(e) is an alkynylene chain as defined above and R_(h) is aheterocyclyl radical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkynyl radical at the nitrogen atom. The alkynylene chain part ofthe heterocyclylalkynyl radical may be optionally substituted as definedabove for an alkynylene chain. The heterocyclyl part of theheterocyclylalkynyl radical may be optionally substituted as definedabove for a heterocyclyl group.

“Heteroaryl” refers to a 3- to 18-membered partially or fully aromaticring radical that comprises one to seventeen carbon atoms and from oneto six heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur. For purposes of this invention, the heteroarylradical may be a monocyclic, bicyclic, tricyclic or tetracyclic ringsystem, which may include fused or bridged ring systems; and thenitrogen, carbon or sulfur atoms in the heteroaryl radical may beoptionally oxidized; the nitrogen atom may be optionally quaternized.The heteroaryl may be attached to the rest of the molecule through anyatom on the ring(s). Examples of heteroaryls include, but are notlimited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl,1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl,benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl,1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl,benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzothienyl (benzothiophenyl),benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from the group consisting of alkyl, alkenyl, alkynyl, halo,haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted aralkenyl, optionally substituted aralkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted cycloalkylalkenyl, optionally substitutedcycloalkylalkynyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R¹⁵—OR¹⁴, —R¹⁵—OC(O)—R¹⁴, —R¹⁵—N(R¹⁴)₂,—R¹⁵—C(O)R¹⁴, —R¹⁵—C(O)OR¹⁴, —R¹⁵—C(O)N(R¹⁴)₂, —R¹⁵—N(R¹⁴)C(O)OR¹⁴,—R¹⁵—N(R¹⁴)C(O)R¹⁴, —R¹⁵—N(R¹⁴)S(O)_(t)R¹⁴ (where t is 1 or 2),—R¹⁵—S(O)_(t)OR¹⁴ (where t is 1 or 2), —R¹⁵—S(O)_(p)R¹⁴ (where p is 0, 1or 2), and —R¹⁵—S(O)_(t)N(R¹⁴)₂ (where t is 1 or 2), where each R¹⁴ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, and each R¹⁵ is independently a direct bond or astraight or branched alkylene or alkenylene chain.

“Polycyclic heteroaryl” is a subset of heteroaryl and refers to aheteroaryl including two, three or four fused or bridged rings, at leastone of which is fully aromatic. Typically, bicyclic heteroaryls can be9- to 12-membered rings, more typically, 9- to 10-membered rings.Tricylic heteroaryls can be 12- to 18-membered rings. Tetracyclicheteroaryl can be 15- or 18-membered rings. A preferred polycyclicheteroaryl is a phenyl ring fused with another ring containing at leastone heteroatom (i.e., a heteroaryl). Another preferred polycyclicheteroaryl is a pyrimidinyl ring fused with a second ring selected fromthe group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl,as defined herein. Specific examples of polycyclic heteroaryl include,but are not limited to, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl,benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl,benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl,cinnolinyl, cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, indazolyl, indolyl,indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl,indolizinyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrazolo[3,4-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl,pyrido[3,4-d]pyrimidinyl, pyrazinyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, and thieno[2,3-c]pyridinyl. Optionally, eachring of the polycyclic heteroaryl may be further substituted with one ormore substituents selected from the group consisting of alkyl, alkenyl,alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano,nitro, optionally substituted aryl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substituted aralkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R¹⁵— R¹⁴, —R¹⁵—OC(O)—R¹⁴, —R¹⁵—N(R¹⁴)₂,—R¹⁵—C(O)R¹⁴, —R¹⁵—C(O)OR¹⁴, —R¹⁵—C(O)N(R¹⁴)₂, —R¹⁵—N(R¹⁴)C(O)OR¹⁴,—R¹⁵—N(R¹⁴)C(O)R¹⁴, —R¹⁵—N(R¹⁴)S(O)_(t)R¹⁴ (where t is 1 or 2),—R¹⁵—S(O)_(t)OR¹⁴ (where t is 1 or 2), —R¹⁵—S(O)_(p)R¹⁴ (where p is 0, 1or 2), and —R¹⁵—S(O)_(t)N(R¹⁴)₂ (where t is 1 or 2), where each R¹⁴ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, and each R¹⁵ is independently a direct bond or astraight or branched alkylene or alkenylene chain.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical may beoptionally substituted as described above for heteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R_(b)R_(i) whereR_(b) is an alkylene chain as defined above and R_(i) is a heteroarylradical as defined above. The heteroaryl part of the heteroarylalkylradical may be optionally substituted as defined above for a heteroarylgroup. The alkylene chain part of the heteroarylalkyl radical may beoptionally substituted as defined above for an alkylene chain.

“Heteroarylalkenyl” refers to a radical of the formula —R_(d)R_(i) whereR_(d) is an alkenylene chain as defined above and R_(i) is a heteroarylradical as defined above. The heteroaryl part of the heteroarylalkenylradical may be optionally substituted as defined above for a heteroarylgroup. The alkenylene chain part of the heteroarylalkenyl radical may beoptionally substituted as defined above for an alkenylene chain.

“Heteroarylalkynyl” refers to a radical of the formula —R_(e)R_(i) whereR_(e) is an alkynylene chain as defined above and R_(i) is a heteroarylradical as defined above. The heteroaryl part of the heteroarylalkynylradical may be optionally substituted as defined above for a heteroarylgroup. The alkynylene chain part of the heteroarylalkynyl radical may beoptionally substituted as defined above for an alkynylene chain.

“Hydroxyalkyl” refers to an alkyl radical as defined above which issubstituted by one or more hydroxy groups (—OH).

“Hydroxyalkenyl” refers to an alkenyl radical as defined above which issubstituted by one or more hydroxy groups (—OH).

“Hydroxyalkenyl” refers to an alkynyl radical as defined above which issubstituted by one or more hydroxy groups (—OH).

Certain chemical groups named herein may be preceded by a shorthandnotation indicating the total number of carbon atoms that are to befound in the indicated chemical group. For example; C₇-C₁₂alkyldescribes an alkyl group, as defined below, having a total of 7 to 12carbon atoms, and C₄-C₁₂cycloalkylalkyl describes a cycloalkylalkylgroup, as defined below, having a total of 4 to 12 carbon atoms. Thetotal number of carbons in the shorthand notation does not includecarbons that may exist in substituents of the group described.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” includes humans and domestic animals, such as cats, dogs,swine, cattle, sheep, goats, horses, rabbits, and the like. Preferably,for purposes of this invention, the mammal is a human.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution. When a functional group is described as “optionallysubstituted,” and in turn, substitutents on the functional group arealso “optionally substituted” and so on, for the purposes of thisinvention, such iterations are limited to five.

“Pharmaceutically acceptable excipient” includes without limitation anyadjuvant, carrier, excipient, glidant, sweetening agent, diluent,preservative, dye/colorant, flavor enhancer, surfactant, wetting agent,dispersing agent, suspending agent, stabilizer, isotonic agent, solvent,or emulsifier which has been approved by the United States Food and DrugAdministration as being acceptable for use in humans or domesticanimals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, benethamine,benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine,triethanolamine, tromethamine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline and caffeine.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, for example,humans. Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Therapeutically effective amount” refers to that amount of a compoundof the invention which, when administered to a mammal, preferably ahuman, is sufficient to effect treatment, as defined below, of a diseaseor condition of interest in the mammal, preferably a human. The amountof a compound of the invention which constitutes a “therapeuticallyeffective amount” will vary depending on the compound, the disease orcondition and its severity, and the age of the mammal to be treated, butcan be determined routinely by one of ordinary skill in the art havingregard to his own knowledge and to this disclosure.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or condition of interest, and includes:

(i) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;

(ii) inhibiting the disease or condition, i.e., arresting itsdevelopment;

(iii) relieving the disease or condition, i.e., causing regression ofthe disease or condition; or

(iv) stabilizing the disease or condition.

As used herein, the terms “disease” and “condition” may be usedinterchangeably or may be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, wherein a more or lessspecific set of symptoms have been identified by clinicians.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centres and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, such as HPLC using a chiralcolumn. When the compounds described herein contain olefinic doublebonds or other centres of geometric asymmetry, and unless specifiedotherwise, it is intended that the compounds include both E and Zgeometric isomers. Likewise, all tautomeric forms are also intended tobe included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

“Atropisomers” are stereoisomers resulting from hindered rotation aboutsingle bonds where the barrier to rotation is high enough to allow forthe isolation of the conformers (Eliel, E. L.; Wilen, S. H.Stereochemistry of Organic Compounds; Wiley & Sons: New York, 1994;Chapter 14). Atropisomerism is significant because it introduces anelement of chirality in the absence of stereogenic atoms. The inventionis meant to encompass atropisomers, for example in cases of limitedrotation around the single bonds emanating from the core thiazolestructure, atropisomers are also possible and are also specificallyincluded in the compounds and/or prodrugs of the invention.

The chemical naming protocol and structure diagrams used herein are amodified form of the I.U.P.A.C. nomenclature system wherein thecompounds of the invention are named herein as derivatives of thecentral core structure, i.e., the thiazole structure. For complexchemical names employed herein, a substituent group is named before thegroup to which it attaches. For example, cyclopropylethyl comprises anethyl backbone with cyclopropyl substituent. In chemical structurediagrams, all bonds are identified, except for some carbon atoms, whichare assumed to be bonded to sufficient hydrogen atoms to complete thevalency.

The numbering system of the ring atoms in diaminothiazole compounds offormula (I) is shown below:

For example, a compound of formula (I) wherein R¹, R⁴ and R⁵ are eachhydrogen, R² is 4-(2-(pyrrolidin-1-yl)ethoxy)phenyl, and R³ is(6,7-dimethoxy)quinazolin-4-yl; i.e., a compound of the followingformula:

is named herein as5-(6,7-dimethoxyquinazolin-4-yl)-N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine.

EMBODIMENTS OF THE INVENTION

Of the various aspects of the invention, as set forth above in theSummary of the Invention, one aspect is the compounds of formula (I), asisolated stereoisomers or mixtures thereof, or pharmaceuticallyacceptable salts thereof. Of this aspect, certain embodiments arepreferred.

Accordingly, one embodiment is a compound of formula (I) wherein:

-   R¹, R⁴ and R⁵ are each hydrogen,-   R² is aryl or heteroaryl, the aryl or heteroaryl being optionally    substituted with one or more substituents selected from the group    consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,    —R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,    —R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or    2), —R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,    —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,    —R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t    is 1 or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹    (where p is 0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or    2);-   R³ is heteroaryl having at least six ring atoms, the heteroaryl    being optionally substituted with one or more substituents selected    from the group consisting of cyano, nitro, halo, haloalkyl, alkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,    —R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,    —R¹⁰—OR¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2),    —R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—OR¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,    —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,    —R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t    is 1 or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹    (where p is 0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or    2);-   each R⁶ and R⁷ are each independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹¹—OR⁹, —R¹¹—CN, —R¹¹—NO₂, —R¹¹—N(R⁹)₂,    —R¹¹—C(O)OR⁹ and —R¹¹—C(O)N(R⁹)₂;-   each R⁹ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted aralkenyl, optionally substituted    aralkynyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl and optionally substituted heteroarylalkynyl;-   each R¹⁰ is independently selected from the group consisting of a    direct bond, an optionally substituted straight or branched alkylene    chain, an optionally substituted straight or branched alkenylene    chain and an optionally substituted straight or branched alkynylene    chain;-   each R¹¹ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain, an    optionally substituted straight or branched alkenylene chain and an    optionally substituted straight or branched alkynylene chain; and-   each R¹² is hydrogen, alkyl, cyano, nitro or —OR⁹.

Of this embodiment, one embodiment is a compound of formula (I) wherein:

-   R¹, R⁴ and R⁵ are each hydrogen,-   R² is aryl optionally substituted with one or more substituents    selected from the group consisting of cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,    —R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,    —R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or    2), —R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,    —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,    —R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t    is 1 or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹    (where p is 0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or    2);-   R³ is heteroaryl having at least six ring atoms, the heteroaryl    being optionally substituted with one or more substituents selected    from the group consisting of cyano, nitro, halo, haloalkyl, alkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,    —R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,    —R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or    2), —R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,    —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,    —R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t    is 1 or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹    (where p is 0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or    2); and-   each R⁵ and R⁷ are each independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹¹—OR⁹, —R¹¹—CN, —R¹¹—NO₂, —R¹¹—N(R⁹)₂,    —R¹¹—C(O)OR⁹ and —R¹¹—C(O)N(R⁹)₂;-   each R⁹ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted aralkenyl, optionally substituted    aralkynyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl and optionally substituted heteroarylalkynyl;-   each R¹⁰ is independently selected from the group consisting of a    direct bond, an optionally substituted straight or branched alkylene    chain, an optionally substituted straight or branched alkenylene    chain and an optionally substituted straight or branched alkynylene    chain;-   each R¹¹ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain, an    optionally substituted straight or branched alkenylene chain and an    optionally substituted straight or branched alkynylene chain; and-   each R¹² is hydrogen, alkyl, cyano, nitro or —OR⁹;-   as isolated stereoisomers or mixtures thereof, as tautomers or    mixtures thereof, or as pharmaceutically acceptable salts, hydrates,    solvates, N-oxides or prodrugs thereof.

Of this embodiment, one embodiment is a compound of formula (I) wherein:

-   R¹, R⁴ and R⁵ are each hydrogen,-   R² is phenyl optionally substituted with one or more substituents    selected from the group consisting of cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,    —R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,    —R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or    2), —R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,    —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,    —R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t    is 1 or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹    (where p is 0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or    2);-   R³ is heteroaryl selected from the group consisting of pyridinyl,    pyrazolo[3,4-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl,    pyrido[3,4-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl,    thieno[3,2-d]pyrimidinyl, quinazolinyl, quinoxalinyl, quinolinyl,    isoquinolinyl and benzo[d]thiazolyl, the heteroaryl being optionally    substituted with one or more substituents selected from the group    consisting of alkyl and —R¹⁰—OR⁹.-   each R⁶ and R⁷ are each independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹¹—OR⁹, —R¹¹—CN, —R¹¹—NO₂, —R¹¹—N(R⁹)₂,    —R¹¹—C(O)OR⁹ and —R¹¹—C(O)N(R⁹)₂;-   each R⁹ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted aralkenyl, optionally substituted    aralkynyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl and optionally substituted heteroarylalkynyl;-   each R¹⁰ is independently selected from the group consisting of a    direct bond, an optionally substituted straight or branched alkylene    chain, an optionally substituted straight or branched alkenylene    chain and an optionally substituted straight or branched alkynylene    chain;-   each R¹¹ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain, an    optionally substituted straight or branched alkenylene chain and an    optionally substituted straight or branched alkynylene chain; and-   each R¹² is hydrogen, alkyl, cyano, nitro or —OR⁹;-   as isolated stereoisomers or mixtures thereof, as tautomers or    mixtures thereof, or as pharmaceutically acceptable salts, hydrates,    solvates, N-oxides or prodrugs thereof.

Of this embodiment, one embodiment is a compound of formula (I) wherein:

-   R¹, R⁴ and R⁵ are each hydrogen,-   R² is phenyl substituted with one or more —OR⁹; and-   each R⁹ is independently selected from the group consisting of alkyl    and optionally substituted heterocyclylalkyl.

Of this embodiment, specific embodiments are compounds of formula (I)selected from the group consisting of:

-   N²-(4-methoxyphenyl)-5-(pyridin-2-yl)thiazole-2,4-diamine;-   5-(quinoxalin-2-yl)-N²-(3,4,5-trimethoxyphenyl)thiazole-2,4-diamine;-   N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(quinoxalin-2-yl)thiazole-2,4-diamine;-   N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(quinazolin-4-yl)thiazole-2,4-diamine;-   5-(quinazolin-4-yl)-N²-(3,4,5-trimethoxyphenyl)thiazole-2,4-diamine;-   5-(isoquinolin-1-yl)-N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine;-   5-(benzo[d]thiazol-2-yl)-N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine;-   5-(6,7-dimethoxyquinazolin-4-yl)-N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine;    and-   N²-(3-chloro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(6,7-dimethoxyquinazolin-4-yl)thiazole-2,4-diamine.

Another embodiment of the compounds of formula (I), as set forth above,is a compound of formula (I) wherein:

-   R¹, R⁴ and R⁵ are each hydrogen;-   R² is phenyl substituted with one or more optionally substituted    heterocyclyl; and-   R³ is heteroaryl selected from the group consisting of pyridinyl,    pyrazolo[3,4-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl,    pyrido[3,4-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl,    thieno[3,2-d]pyrimidinyl, quinazolinyl, quinoxalinyl, quinolinyl,    isoquinolinyl and benzo[d]thiazolyl, the heteroaryl being optionally    substituted with one or more substituents selected from the group    consisting of alkyl and —OR⁹; and-   each R⁹ is independently alkyl.

Of this embodiment, one embodiment is a compound of formula (I) wherein:

-   R² is phenyl substituted with one or more N-heterocyclyl optionally    substituted with one or more substituents selected from the group    consisting of alkyl, cycloalkyl and —C(O)R⁹; and-   each R⁹ is independently alkyl.

Of this embodiment, specific embodiments are compounds of formula (I)selected from the group consisting of:

-   5-(isoquinolin-1-yl)-N²-(4-morpholinophenyl)thiazole-2,4-diamine;-   5-(6,7-dimethoxyquinazolin-4-yl)-N²-(4-morpholinophenyl)thiazole-2,4-diamine;-   5-(6,7-dimethoxyquinazolin-4-yl)-N²-(4-(4-methyl    piperazin-1-yl)phenyl)thiazole-2,4-diamine;-   N²-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-5-(thieno[3,2-d]pyrimidin-4-yl)thiazole-2,4-diamine;    and-   N²-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-5-(6,7-dimethoxyquinazolin-4-yl)thiazole-2,4-diamine.

Another embodiment of the compounds of formula (I), as set forth above,is a compound of formula (I) wherein:

-   R¹, R⁴ and R⁵ are each hydrogen;-   R² is phenyl substituted with one or more substituents selected from    the group consisting of optionally substituted heterocyclylalkyl,    halo, —OR⁹ and —C(O)R⁹; and-   R³ is heteroaryl selected from the group consisting of pyridinyl,    pyrazolo[3,4-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl,    pyrido[3,4-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl,    thieno[3,2-d]pyrimidinyl, quinazolinyl, quinoxalinyl, quinolinyl,    isoquinolinyl and benzo[d]thiazolyl, the heteroaryl being optionally    substituted with one or more substituents selected from the group    consisting of alkyl and —OR⁹; and-   each R⁹ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted aralkenyl, optionally substituted    aralkynyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl.

Another embodiment of the compounds of formula (I), as set forth above,is a compound of formula (I), wherein:

-   R¹, R⁴ and R⁵ are each hydrogen,-   R² is heteroaryl optionally substituted with one or more    substituents selected from the group consisting of cyano, nitro,    halo, haloalkyl, alkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN,    —R¹⁰—OR¹¹—C(O)OR⁹, —R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹    (where p is 0, 1 or 2), —R¹⁰—O—R¹¹—N(R⁶)R⁷,    —R¹⁰—OR¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹, —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹,    —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷, —R¹⁰—N(R⁶)C(O)OR¹⁴,    —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1 or 2),    —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is 0,    1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2);-   R³ is heteroaryl having at least six ring atoms, the heteroaryl    being optionally substituted with one or more substituents selected    from the group consisting of cyano, nitro, halo, haloalkyl, alkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,    —R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,    —R¹⁰—OR¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2),    —R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—OR¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,    —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,    —R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t    is 1 or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹    (where p is 0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or    2);-   each R⁵ and R⁷ are each independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹¹—OR⁹, —R¹¹—CN, —R¹¹—NO₂, —R¹¹—N(R⁹)₂,    —R¹¹—C(O)OR⁹ and —R¹¹—C(O)N(R⁹)₂;-   each R⁹ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted aralkenyl, optionally substituted    aralkynyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl and optionally substituted heteroarylalkynyl;-   each R¹⁰ is independently selected from the group consisting of a    direct bond, an optionally substituted straight or branched alkylene    chain, an optionally substituted straight or branched alkenylene    chain and an optionally substituted straight or branched alkynylene    chain;-   each R¹¹ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain, an    optionally substituted straight or branched alkenylene chain and an    optionally substituted straight or branched alkynylene chain; and-   each R¹² is hydrogen, alkyl, cyano, nitro or —OR⁹;-   as isolated stereoisomers or mixtures thereof, as tautomers or    mixtures thereof, or as pharmaceutically acceptable salts, hydrates,    solvates, N-oxides or prodrugs thereof.

A further embodiment of the compounds of formula (I), as set forthabove, is directed to compounds of formula (I) wherein R³ is polycyclicheteroaryl. More specifically, R³ is pyrimidin-4-yl or pyridin-2-ylfused with a second ring selected from the group consisting ofcycloalkyl, heterocyclyl, aryl and heteroaryl. Thus, the compounds inaccordance with this embodiment can be represented by formula (Ia):

wherein:

-   X is N or CH;-   w is 0, 1, 2, 3, 4, 5, 6, 7 or 8;-   R¹, R^(3a), R⁴ and R⁵ are each independently hydrogen, alkyl, aryl,    aralkyl, —C(O)R¹⁰ or —C(O)N(R⁶)R⁷;-   R² is aryl or heteroaryl, the aryl or heteroaryl being optionally    substituted with one or more substituents selected from the group    consisting of cyano, nitro, halo, haloalkyl, alkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,    —R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,    —R¹⁰—OR¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2),    —R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—OR¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,    —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,    —R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t    is 1 or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹    (where p is 0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or    2);-   A is cycloalkyl, heterocyclyl, heteroaryl or aryl;-   each R^(3b) is independently selected from the group consisting of    cyano, nitro, halo, haloalkyl, alkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted heteroaryl, optionally substituted heteroarylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—O—R¹¹—OR⁹,    —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹, —R¹⁰—OR¹¹—C(O)N(R⁶)R⁷,    —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2), —R¹⁰—O—R¹¹—N(R⁶)R⁷,    —R¹⁰—OR¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹, —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹,    —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷, —R¹⁰—N(R⁶)C(O)OR¹⁴,    —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1 or 2),    —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is 0,    1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2);-   each R⁶ and R⁷ are each independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹¹—OR⁹, —R¹¹—CN, —R¹¹—NO₂, —R¹¹—N(R⁹)₂,    —R¹¹—C(O)OR⁹ and —R¹¹—C(O)N(R⁹)₂;-   each R⁹ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted aralkenyl, optionally substituted    aralkynyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl and optionally substituted heteroarylalkynyl;-   each R¹⁰ is independently selected from the group consisting of a    direct bond, an optionally substituted straight or branched alkylene    chain, an optionally substituted straight or branched alkenylene    chain and an optionally substituted straight or branched alkynylene    chain;-   each R¹¹ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain, an    optionally substituted straight or branched alkenylene chain and an    optionally substituted straight or branched alkynylene chain; and-   each R¹² is hydrogen, alkyl, cyano, nitro or —OR⁹;-   as isolated stereoisomers or mixtures thereof, as tautomers or    mixtures thereof, or as pharmaceutically acceptable salts, hydrates,    solvates, N-oxides or prodrugs thereof.

Of this embodiment, one embodiment is a compound of formula (Ia)wherein:

-   w is 0, 1, 2, 3 or 4;-   R¹, R^(3a), R⁴ and R⁵ are each hydrogen;-   R² is phenyl optionally substituted with one or more substituents    selected from the group consisting of cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,    —R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—OR¹¹—C(O)OR⁹,    —R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or    2), —R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,    —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,    —R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t    is 1 or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹    (where p is 0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or    2);-   A is aryl;-   each R^(3b) is independently selected from the group consisting of    cyano, nitro, halo, haloalkyl, alkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted heteroaryl, optionally substituted heteroarylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—O—R¹¹—OR⁹,    —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹, —R¹⁰—OR¹¹—C(O)N(R⁶)R⁷,    —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2), —R¹⁰—O—R¹¹—N(R⁶)R⁷,    —R¹⁰—OR¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹, —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹,    —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷, —R¹⁰—N(R⁶)C(O)OR¹⁴,    —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1 or 2),    —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is 0,    1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); and-   R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined above.

Of this embodiment, one embodiment is a compound of formula (Ia)wherein:

-   X is N;-   w is 0, 1 or 2;-   R¹, R^(3a), R⁴ and R⁵ are each hydrogen;-   R² is phenyl substituted with one or more substituents selected from    the group consisting of —OR⁹ and N-heterocyclyl optionally    substituted with one or more substituents selected from the group    consisting of alkyl, cycloalkyl and —C(O)R⁹;-   A is phenyl;-   each R^(3b) is independently —OR⁹; and-   each R⁹ is independently alkyl or heterocyclylalkyl.

Of this embodiment, specific embodiments are compounds of formula (Ia)selected from the group consisting of:

-   5-(6,7-dimethoxyquinazolin-4-yl)-N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine;-   N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(quinazolin-4-yl)thiazole-2,4-diamine;-   5-(quinazolin-4-yl)-N²-(3,4,5-trimethoxyphenyl)thiazole-2,4-diamine;-   5-(6,7-dimethoxyquinazolin-4-yl)-N²-(4-morpholinophenyl)thiazole-2,4-diamine;-   5-(6,7-dimethoxyquinazolin-4-yl)-N²-(4-(4-methyl    piperazin-1-yl)phenyl)thiazole-2,4-diamine;-   N²-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-5-(6,7-dimethoxyquinazolin-4-yl)thiazole-2,4-diamine;    and-   N²-(3-chloro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(6,7-dimethoxyquinazolin-4-yl)thiazole-2,4-diamine.

Another embodiment of the compounds of formula (I), as set forth above,is a compound of formula (Ia), wherein:

-   X is CH;-   w is 0;-   R¹, R^(3a), R^(3b), R⁴ and R⁵ are each hydrogen;-   R² is phenyl substituted with one or more substituents selected from    the group consisting of —OR⁹ and N-heterocyclyl optionally    substituted with one or more substituents selected from the group    consisting of alkyl, cycloalkyl and —C(O)R⁹;-   A is phenyl;-   each R⁹ is independently alkyl or heterocyclylalkyl.

Of this embodiment, specific embodiments are compounds of formula (Ia)selected from the group consisting of:

-   5-(isoquinolin-1-yl)-N²-(4-morpholinophenyl)thiazole-2,4-diamine;    and-   5-(isoquinolin-1-yl)-N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine.

Another embodiment of the compounds of formula (I), as set forth above,is a compound of formula (Ia) wherein:

-   w is 0, 1, 2, 3 or 4;-   R¹, R^(3a), R⁴ and R⁵ are each hydrogen;-   R² is phenyl optionally substituted with one or more substituents    selected from the group consisting of cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,    —R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,    —R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or    2), —R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,    —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,    —R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t    is 1 or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹    (where p is 0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or    2);-   A is heteroaryl;-   each R^(3b) is independently selected from the group consisting of    cyano, nitro, halo, haloalkyl, alkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted heteroaryl, optionally substituted heteroarylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—O—R¹¹—OR⁹,    —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹, —R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷,    —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2), —R¹⁰—O—R¹¹—N(R⁶)R⁷,    —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹, —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹,    —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷, —R¹⁰—N(R⁶)C(O)OR¹⁴,    —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1 or 2),    —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is 0,    1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); and-   R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined above.

Of this embodiment, one embodiment is a compound of formula (Ia)wherein:

-   X is N;-   w is 0;-   R¹, R^(3a), R^(3b), R⁴ and R⁵ are each hydrogen;-   R² is phenyl substituted with one or more N-heterocyclyl optionally    substituted with one or more substituents selected from the group    consisting of alkyl, cycloalkyl and —C(O)R⁹;-   A is thienyl; and-   each R⁹ is independently alkyl.

Of this embodiment, a specific embodiment isN²-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-5-(thieno[3,2-d]pyrimidin-4-yl)thiazole-2,4-diamine.

Of the various aspects of the invention, as set forth above in theSummary of the Invention, another aspect is the pharmaceuticalcompositions comprising a pharmaceutically acceptable excipient and atherapeutically effective amount of a compound of formula (I), as setforth above in the Summary of the Invention. Of this aspect, certainembodiments are preferred.

One embodiment of these pharmaceutical compositions is wherein thecompound of formula (I) therein is selected from any one embodiment ofthe compound of formula (I), as set forth above, or from any combinationof embodiments of the compound of formula (I), as set forth above.

Of the various aspects of the invention, as set forth above in theSummary of the Invention, one aspect is the methods of treating adisease or condition associated with Axl activity in a mammal, whereinthe method comprises administering to a mammal in need thereof atherapeutically effective amount of a compound of formula (I), as setforth above in the Summary of the Invention. Of this aspect, certainembodiments are preferred.

One embodiment of this aspect is the method wherein the disease orcondition is selected from the group consisting of rheumatoid arthritis,vascular disease, vascular injury, psoriasis, visual impairment due tomacular degeneration, diabetic retinopathy, retinopathy of prematurity,kidney disease, osteoporosis, osteoarthritis and cataracts.

Another embodiment of this aspect is the method wherein a manifestationof the disease or condition is solid tumor formation in said mammal.

Another embodiment of this aspect is the method wherein the disease orcondition is selected from the group consisting of breast carcinoma,renal carcinoma, endometrial carcinoma, ovarian carcinoma, thyroidcarcinoma, non-small cell lung carcinoma, and uveal melanoma.

Another embodiment of this aspect is the method wherein a manifestationof the disease or condition is liquid tumor formation in said mammal.

Another embodiment of this aspect is the method wherein the disease orcondition is myeloid leukemia or lymphoma.

Another embodiment of this aspect is the method wherein the disease orcondition is endometriosis.

Another embodiment of this aspect is the method wherein the compounds offormula (I) utilized therein is selected from any one embodiment of thecompound of formula (I), as set forth above, or from any combination ofembodiments of the compound of formula (I), as set forth above.

Another embodiment of this aspect is the methods of treating a diseaseor condition associated with Axl activity by administering to the mammala therapeutically effective amount of a pharmaceutical composition ofthe invention, as set forth above in the Summary of the Invention,wherein the disease or condition is selected from the group consistingof rheumatoid arthritis, vascular disease/injury (including but notlimited to restenosis, atherosclerosis and thrombosis), psoriasis,visual impairment due to macular degeneration, diabetic retinopathy orretinopathy of prematurity, kidney disease (including but not limited toglomerulonephritis, diabetic nephropathy and renal transplantrejection), osteoporosis, osteoarthritis and cataracts.

Another embodiment of this aspect is the methods of treating a diseaseor condition associated with Axl activity by administering to the mammala therapeutically effective amount of a pharmaceutical composition ofthe invention, as set forth above in the Summary of the Invention,wherein the disease or condition is selected from the group consistingof breast carcinoma, renal carcinoma, endometrial carcinoma, ovariancarcinoma, thyroid carcinoma, non-small cell lung carcinoma, melanoma,prostate carcinoma, sarcoma, gastric cancer, uveal melanoma, myeloidleukemia and lymphoma.

Another embodiment of this aspect is the methods of treating a diseaseor condition associated with Axl activity by administering to the mammalof therapeutically effective amount of a pharmaceutical composition ofthe invention, as set forth above in the Summary of the Invention,wherein the disease or condition is endometriosis.

It is understood that any embodiment of the compounds of formula (I), asset forth above, and any specific substituent set forth herein for a R¹,R², R³, R⁴ and R⁵ group in the compounds of formula (I), as set forthabove, may be independently combined with other embodiments and/orsubstituents of compounds of formula (I) to form embodiments of theinventions not specifically set forth above. In addition, in the eventthat a list of substitutents is listed for any particular R group in aparticular embodiment and/or claim, it is understood that eachindividual substituent may be deleted from the particular embodimentand/or claim and that the remaining list of substituents will beconsidered to be within the scope of the invention.

Specific embodiments of the invention are described in more detail belowin the following sections.

Utility and Testing of the Compounds of the Invention

The oncogenic RTK, Axl, was recently identified, using aretroviral-based functional genetic screening protocol, as a regulatorof haptotactic migration, which is a key event in angiogenesis. Axlinhibition by RNAi-mediated silencing blocked endothelial cellmigration, proliferation and in vitro tube formation. Theseobservations, which were disclosed at the American Association CancerResearch General Meeting, Apr. 16-20, 2005, Anaheim, Calif., and The 7thAnnual Symposium on Anti-Angiogenic Agents, Feb. 10-13, 2005, San Diego,Calif.; (Requirement for The Receptor Tyrosine Kinase Axl inAngiogenesis and Tumor Growth, Holland, S. J., et al.,), weresubstantiated by an in vivo study which demonstrated that stable,shRNAi-mediated Axl knockdown impaired formation of functional humanblood vessels in a mouse model of human angiogenesis. These observationswere published in a peer reviewed journal (Holland, S. J., et al.,“Multiple roles for the receptor tyrosine kinase axl in tumorformation.” Cancer Res. (2005), Vol. 65, pp 9294-303. These observationsare also disclosed in U.S. Published Patent Application 2005/0118604 andEuropean Patent Application 1 563 094, the disclosures of which areincorporated in full by reference. Axl signaling, therefore, impactsmultiple functions required for neovascularization in vitro, andregulates angiogenesis in vivo. Regulation of these pro-angiogenicprocesses required the catalytic activity of Axl. Thus, Axl-mediatedangiogenic stimulation would be amenable to modulation by a smallmolecule inhibitor of Axl catalytic activity.

Accordingly, the compounds of the invention are small moleculeinhibitors of Axl catalytic activity, and are therefore useful intreating diseases and conditions which are associated with Axl catalyticactivity including those diseases and conditions which are characterizedby angiogenesis and/or cell proliferation. In particular, the compoundsof the invention and pharmaceutical compositions of the invention areuseful in treating diseases and conditions which are alleviated by themodulation of Axl activity. For purposes of this invention, diseases andconditions which are alleviated by the “modulation of Axl activity”includes diseases and conditions which are alleviated by a decrease inAxl activity and diseases and conditions which are alleviated by anincrease in Axl activity. Preferably such diseases and conditions arealleviated by a decrease in Axl activity. Diseases and conditions whichare alleviated by the modulation of Axl activity include, but are notlimited to, solid tumors, including, but not limited to, breast, renal,endometrial, ovarian, thyroid, and non-small cell lung carcinoma,melanoma, prostate carcinoma, sarcoma, gastric cancer and uvealmelanoma; liquid tumors, including but not limited to, leukemias(particularly myeloid leukemias) and lymphomas; endometriosis, vasculardisease/injury (including but not limited to restenosis, atherosclerosisand thrombosis), psoriasis; visual impairment due to maculardegeneration; diabetic retinopathy and retinopathy of prematurity;kidney disease (including but not limited to glomerulonephritis,diabetic nephropathy and renal transplant rejection), rheumatoidarthritis; osteoarthritis, osteoporosis and cataracts.

In addition to the foregoing, the compounds of the invention are usefulin treating diseases and conditions which are affected by the followingbiological processes: Invasion, migration, metastasis, or drugresistance as manifested in cancer; stem cell biology as manifested incancer; invasion, migration, adhesion, or angiogenesis as manifested inendometriosis; vascular remodeling as manifested in cardiovasculardisease, hypertension or vascular injury; bone homeostatasis asmanifested in osteoporosis or osteoarthritis; viral infection asmanifested, for example, in ebola virus infection; or differentiation asmanifested in obesity. The compounds of the invention may also be usedto modulate inflammatory processes by treating sepsis, acting as vaccineadjuvants, and/or potentiating the immune response in immuno-compromisedpatients.

The following animal models provide guidance to one of ordinary skill inthe art in testing the compounds of the invention for their use intreating the disease or condition indicated.

The compounds of the invention may be tested for their use in treatingleukemias and lymphomas by testing the compounds in the xenograft inSCID mouse model using human Axl-expressing cancer cell lines including,but not limited to, HeLa, MDA-MB-231, SK-OV-3, OVCAR-8, DU145, H1299,ACHN, A498 and Caki-1.

The compounds of the invention may be tested for their use in treatingleukemias in the xenograft in SCID or nu/nu mouse model using humanAxl-expressing AML and CML leukemia cell lines.

The compounds of the invention may be tested for their use in treatingendometriosis by using the syngenic mouse model of endometriosis (seeSomigliana, E. et al., “Endometrial ability to implant in ectopic sitescan be prevented by interleukin-12 in a murine model of endometriosis”,Hum. Reprod. (1999), Vol. 14, No. 12, pp. 2944-50). The compounds mayalso be tested for their use in treating endometriosis by using the ratmodel of endometriosis (see Lebovic, D. I. et al., “Peroxisomeproliferator-activated receptor-gamma induces regression of endometrialexplants in a rat model of endometriosis”, Fertil. Steril. (2004), 82Suppl 3, pp. 1008-13).

The compounds of the invention may be tested for their use in treatingrestenosis by using the balloon-injured rate carotid artery model (seeKim, D. W. et al., “Novel oral formulation of paclitaxel inhibitsneointimal hyperplasia in a rat carotid artery injury model”,Circulation (2004), Vol. 109, No. 12, pp. 1558-63, Epub 2004 Mar. 8).

The compounds of the invention may also be tested for their use intreating restenosis by using the percutaneous transluminal coronaryangioplasty in apoE deficient mouse model (see von der Thusen, J. H. etal., “Adenoviral transfer of endothelial nitric oxide synthaseattenuates lesion formation in a novel murine model of postangioplastyrestenosis”, Arterioscler. Thromb. Vasc. Biol. (2004), Vol. 24, No. 2,pp. 357-62).

The compounds of the invention may be tested for their use in treatingatherosclerosis/thrombosis in the ApoE deficient mouse model (seeNakashima, Y. et al., “ApoE-deficient mice develop lesions of all phasesof atherosclerosis throughout the arterial tree”, Arterioscler. Thromb.(1994), Vol. 14, No. 1, pp. 133-40).

The compounds of the invention may also be tested for their use intreating thrombosis using the collagen-epinephrin-induced pulmonarythromboembolism model and the stasis induced venous thrombosis model(see Angelillo-Scherrer A. et al., “Role of Gas6 receptors in plateletsignaling during thrombus stabilization and implications forantithrombotic therapy”, J Clin Invest. (2005), Vol. 115, pp. 237-46).

The compounds of the invention may be tested for their use in treatingpsoriasis by using the SCID mouse model or the human skin model ofpsoriasis (see Nickoloff, B. J. et al., “Severe combinedimmunodeficiency mouse and human psoriatic skin chimeras. Validation ofa new animal model”, Am. J. Pathol. (1995), Vol. 146, No. 3, pp. 580-8).

The compounds of the invention may be tested for their use in treatingage-related macular degeneration or diabetic retinopathy by using therat corneal angiogenesis model (see Sarayba M A, Li L, Tungsiripat T,Liu N H, Sweet P M, Patel A J, Osann K E, Chittiboyina A, Benson S C,Pershadsingh H A, Chuck R S. Inhibition of corneal neovascularization bya peroxisome proliferator-activated receptor-gamma ligand. Exp Eye Res.(2005 March), Vol. 80, No. 3, pp. 435-42) or the laser-induced mousechoroidal neovasculation model (see Bora, P. S., et al., “Immunotherapyfor choroidal neovascularization in a laser-induced mouse modelsimulating exudative (wet) macular degeneration”, Proc. Natl. Acad. Sci.U.S.A. (2003), Vol. 100, No. 5, pp. 2679-84, Epub 2003 Feb. 14).

The compounds of the invention may be tested for their use in treatingretinopathy of prematurity in the mouse retinopathy of prematurity model(see Smith, L. E. et al., “Oxygen-induced retinopathy in the mouse”,Invest. Opthalmol. Vis. Sci. (1994), Vol. 35, No. 1, pp. 101-11).

The compounds of the invention may be tested for their use in treatingglomerulonephritis or diabetic nephropathy in the ratanti-Thy1.1-induced experimental mesengial proliferativeglomerulonephritis model (see Smith, L. E. et al. cited above).

The compounds of the invention may be tested for their use in treatingrenal transplant rejection by using a rat model of chronic renaltransplant rejection (see Yin, J. L. et al., “Expression of growtharrest-specific gene 6 and its receptors in a rat model of chronic renaltransplant rejection”, Transplantation (2002), Vol. 73, No. 4, pp.657-60).

The compounds of the invention may be tested for their use in treatingrheumatoid arthritis by using the CAIA mouse model (see Phadke, K. etal., “Evaluation of the effects of various anti-arthritic drugs on typeII collagen-induced mouse arthritis model”, Immunopharmacology (1985),Vol. 10, No. 1, pp. 51-60).

The compounds of the invention may be tested for their use in treatingosteoarthritis by using the STR/ORT mouse model (see Brewster, M. etal., “Ro 32-3555, an orally active collagenase selective inhibitor,prevents structural damage in the STR/ORT mouse model ofosteoarthritis”, Arthritis. Rheum. (1998), Vol. 41, No. 9, pp. 1639-44).

The compounds of the invention may be tested for their use in treatingosteoporosis by using the ovariectomized rat model (see Wronski, T. J.et al., “Endocrine and pharmacological suppressors of bone turnoverprotect against osteopenia in ovariectomized rats”, Endocrinology(1989), Vol. 125, no. 2, pp 810-6) or the ovariectomized mouse model(see Alexander, J. M. et al., “Human parathyroid hormone 1-34 reversesbone loss in ovariectomized mice”, J Bone Miner Res. (2001), Vol. 16,no. 9, pp 1665-73; Fujioka, M. et al., “Equol, a metabolite of daidzein,inhibits bone loss in ovariectomized mice”, J Nutr. (2004), Vol. 134,No. 10, pp. 2623-7).

The compounds of the invention may be tested for their use in treatingcataracts by using the H₂O₂-induced model (see Kadoya, K. et al., “Roleof calpain in hydrogen peroxide induced cataract”, Curr. Eye Res.(1993), Vol. 12, No. 4, pp. 341-6) or the Emory mouse model (see Sheets,N. L. et al., “Cataract- and lens-specific upregulation of ARK receptortyrosine kinase in Emory mouse cataract”, Invest. Opthalmol. Vis. Sci.(2002), Vol. 43, No. 6, pp. 1870-5).

Pharmaceutical Compositions of the Invention and Administration

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration of agents for serving similar utilities. Thepharmaceutical compositions of the invention can be prepared bycombining a compound of the invention with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, buccal, rectal, vaginal, andintranasal. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. Pharmaceutical compositions of the invention areformulated so as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the invention inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington:

The Science and Practice of Pharmacy, 20th Edition (Philadelphia Collegeof Pharmacy and Science, 2000). The composition to be administered will,in any event, contain a therapeutically effective amount of a compoundof the invention, or a pharmaceutically acceptable salt thereof, fortreatment of a disease or condition of interest in accordance with theteachings of this invention.

A pharmaceutical composition of the invention may be in the form of asolid or liquid. In one aspect, the carrier(s) are particulate, so thatthe compositions are, for example, in tablet or powder form. Thecarrier(s) may be liquid, with the compositions being, for example, anoral oil, an injectable liquid or an aerosol, which is useful in, forexample, inhalatory administration.

When intended for oral administration, the pharmaceutical composition ispreferably in either solid or liquid form, where semi-solid,semi-liquid, suspension and gel forms are included within the formsconsidered herein as either solid or liquid.

As a solid composition for oral administration, the pharmaceuticalcomposition may be formulated into a powder, granule, compressed tablet,pill, capsule, chewing gum, wafer or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following may be present:binders such as carboxymethylcellulose, ethyl cellulose,microcrystalline cellulose, gum tragacanth or gelatin; excipients suchas starch, lactose or dextrins, disintegrating agents such as alginicacid, sodium alginate, Primogel, corn starch and the like; lubricantssuch as magnesium stearate or Sterotex; glidants such as colloidalsilicon dioxide; sweetening agents such as sucrose or saccharin; aflavoring agent such as peppermint, methyl salicylate or orangeflavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, forexample, a gelatin capsule, it may contain, in addition to materials ofthe above type, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition may be in the form of a liquid, forexample, an elixir, syrup, solution, emulsion or suspension. The liquidmay be for oral administration or for delivery by injection, as twoexamples. When intended for oral administration, preferred compositioncontain, in addition to the present compounds, one or more of asweetening agent, preservatives, dye/colorant and flavor enhancer. In acomposition intended to be administered by injection, one or more of asurfactant, preservative, wetting agent, dispersing agent, suspendingagent, buffer, stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition of the invention intended for eitherparenteral or oral administration should contain an amount of a compoundof the invention such that a suitable dosage will be obtained.Typically, this amount is at least 0.01% of a compound of the inventionin the composition. When intended for oral administration, this amountmay be varied to be between 0.1 and about 70% of the weight of thecomposition. Preferred oral pharmaceutical compositions contain betweenabout 4% and about 75% of the compound of the invention. Preferredpharmaceutical compositions and preparations according to the presentinvention are prepared so that a parenteral dosage unit contains between0.01 to 10% by weight of the compound prior to dilution of theinvention.

The pharmaceutical composition of the invention may be intended fortopical administration, in which case the carrier may suitably comprisea solution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, bee wax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device. Topical formulations may contain aconcentration of the compound of the invention from about 0.1 to about10% w/v (weight per unit volume).

The pharmaceutical composition of the invention may be intended forrectal administration, in the form, for example, of a suppository, whichwill melt in the rectum and release the drug. The composition for rectaladministration may contain an oleaginous base as a suitablenonirritating excipient. Such bases include, without limitation,lanolin, cocoa butter and polyethylene glycol.

The pharmaceutical composition of the invention may include variousmaterials, which modify the physical form of a solid or liquid dosageunit. For example, the composition may include materials that form acoating shell around the active ingredients. The materials that form thecoating shell are typically inert, and may be selected from, forexample, sugar, shellac, and other enteric coating agents.Alternatively, the active ingredients may be encased in a gelatincapsule.

The pharmaceutical composition of the invention in solid or liquid formmay include an agent that binds to the compound of the invention andthereby assists in the delivery of the compound. Suitable agents thatmay act in this capacity include a monoclonal or polyclonal antibody, aprotein or a liposome.

The pharmaceutical composition of the invention may comprise dosageunits that can be administered as an aerosol. The term aerosol is usedto denote a variety of systems ranging from those of colloidal nature tosystems consisting of pressurized packages. Delivery may be by aliquefied or compressed gas or by a suitable pump system that dispensesthe active ingredients. Aerosols of compounds of the invention may bedelivered in single phase, bi-phasic, or tri-phasic systems in order todeliver the active ingredient(s). Delivery of the aerosol includes thenecessary container, activators, valves, subcontainers, and the like,which together may form a kit. One of ordinary skill in the art, withoutundue experimentation may determine preferred aerosols.

The pharmaceutical compositions of the invention may be prepared bymethodology well known in the pharmaceutical art. For example, apharmaceutical composition intended to be administered by injection canbe prepared by combining a compound of the invention with sterile,distilled water so as to form a solution. A surfactant may be added tofacilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that non-covalently interact with the compoundof the invention so as to facilitate dissolution or homogeneoussuspension of the compound in the aqueous delivery system.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors including the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particular disorderor condition; and the subject undergoing therapy. Generally, atherapeutically effective daily dose is (for a 70 kg mammal) from about0.001 mg/kg (i.e., 0.07 mg) to about 100 mg/kg (i.e., 7.0 gm);preferably a therapeutically effective dose is (for a 70 kg mammal) fromabout 0.01 mg/kg (i.e., 0.7 mg) to about 50 mg/kg (i.e., 3.5 gm); morepreferably a therapeutically effective dose is (for a 70 kg mammal) fromabout 1 mg/kg (i.e., 70 mg) to about 25 mg/kg (i.e., 1.75 gm).

Compounds of the invention, or pharmaceutically acceptable derivativesthereof, may also be administered simultaneously with, prior to, orafter administration of one or more other therapeutic agents. Suchcombination therapy includes administration of a single pharmaceuticaldosage formulation which contains a compound of the invention and one ormore additional active agents, as well as administration of the compoundof the invention and each active agent in its own separatepharmaceutical dosage formulation. For example, a compound of theinvention and the other active agent can be administered to the patienttogether in a single oral dosage composition such as a tablet orcapsule, or each agent administered in separate oral dosageformulations. Where separate dosage formulations are used, the compoundsof the invention and one or more additional active agents can beadministered at essentially the same time, i.e., concurrently, or atseparately staggered times, i.e., sequentially; combination therapy isunderstood to include all these regimens.

Preparation of the Compounds of the Invention

The following Reaction Schemes illustrate methods to make compounds ofthis invention, i.e., compounds of formula (I):

where R¹, R², R³, R⁴ and R⁵ are described above in the Summary of theInvention, as an isolated stereoisomer or mixture thereof, or apharmaceutically acceptable salt thereof. It is understood that in thefollowing Reaction Schemes, combinations of substituents and/orvariables of the depicted formulae are permissible only if suchcontributions result in stable compounds.

It will also be appreciated by those skilled in the art that in theprocesses described below the functional groups of intermediatecompounds may need to be protected by suitable protecting groups. Suchfunctional groups include hydroxy, amino, mercapto and carboxylic acid.Suitable protecting groups for hydroxy include trialkylsilyl ordiarylalkylsilyl (for example, t-butyldimethylsilyl,t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, andthe like. Suitable protecting groups for amino, amidino and guanidinoinclude benzyl, t-butoxycarbonyl, benzyloxycarbonyl, and the like.Suitable protecting groups for mercapto include —C(O)—R″ (where R″ isalkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like.Suitable protecting groups for carboxylic acids include alkyl, aryl orarylalkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are known to one of ordinary skill in the art and asdescribed herein.

The use of protecting groups is described in detail in Greene, T. W. andP. G. M. Wuts, Greene's Protective Groups in Organic Synthesis (1999),3rd Ed., Wiley. As one of skill in the art would appreciate, theprotecting group may also be a polymer resin such as a Wang resin, Rinkresin or a 2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this invention may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds of theinvention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds of thisinvention are included within the scope of the invention.

It is understood that one of ordinary skill in the art would be able tomake the compounds of the invention by methods similar to the methodsdescribed herein or by methods known to one of ordinary skill in theart. It is also understood that one of ordinary skill in the art wouldbe able to make in a similar manner as described below other compoundsof formula (I) not specifically illustrated below by using theappropriate starting components and modifying the parameters of thesynthesis as needed. In general, starting components may be obtainedfrom sources such as Sigma Aldrich, Lancaster Synthesis, Inc.,Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. orsynthesized according to sources known to those skilled in the art (see,for example, Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, 5th edition (Wiley, December 2000)) or prepared as describedin this invention. ¹H NMR spectra were recorded in CDCl₃, DMSO-d₆,CD₃OD, Acetone-d₆ with trimethylsilane (TMS) as internal reference usingGemini 300 MHz instrument. Reagents and solvents were purchased fromcommercial sources and used without further purification. Flash columnchromatography was conducted using silica gel (230-400 mesh) under apositive pressure of nitrogen. LCMS spectra for purity and mass wererecorded using Waters LCMS instruments. Deionized water was used todilute the reactions and wash the products. Brine used was prepared bydissolving sodium chloride into deionized water to saturation point.

In the following Reaction Schemes, the following common abbreviationsare used:

NBS for N-bromosuccinimide

t-BuOH for t-butanol

ACN for acetonitrile

hν for light irradiation

BPO for benzoyl peroxide

DCM for dichloromethane

rt for ambient temperature (about 20-30° C.)

Compounds of formula (I), as set forth below in Reaction Scheme 1, areprepared as illustrated below in Reaction Scheme 1 where R¹, R⁴ and R⁵are each independently hydrogen, R² is aryl or heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of cyano, nitro, halo, haloalkyl, alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,—R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,—R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2),—R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,—R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,—R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); and R³ isheteroaryl having at least six ring atoms, the heteroaryl beingoptionally substituted with one or more substituents selected from thegroup consisting of cyano, nitro, halo, haloalkyl, alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,—R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—OR¹¹—CN, —R¹⁰—OR¹¹—C(O)OR⁹,—R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2),—R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—OR¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,—R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,—R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)R⁹ (where t is 1 or2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is 0,1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); where each R⁶,R⁷, R⁸, R⁹, R¹⁰ and R¹¹ is as defined above in the Summary of theInvention:

Aryl or heteroaryl amines of formula (A), and compounds of formula (D)are commercially available, or can be prepared by methods known to oneskilled in the art, or by methods disclosed herein.

In general, compounds of formula (I) can be prepared by reacting an arylor heteroaryl isothiocyanate of formula (C), a bromomethyl heteroaryl offormula (E) and a cyanamide (F).

More specifically, aryl isothiocyanate of formula (C) can be prepared,for example, by treating an aryl amine or heteroaryl amine of formula(A) (e.g., an appropriately substituted aniline) with a reagent thatconverts the amino group to the isothiocyanate group. Such reagents areknown to one skilled in the art and include, but are not limited to,carbon disulfide, thiophosgene, 1,1′-thiocarbonyldi-2(1H)-pyridone (B),and thiocarbonyl diimidazole.

Bromomethyl heteroaryl of formula (E) can be prepared, for example, bybrominating a methyl-substituted heteroaryl of formula (D) in a radicalinitiated reaction. Methyl-substituted heteroaryls are commerciallyavailable or can be prepared by known methods in the art. NBS can beused as a brominating reagent. The reaction can be effected by radicalinitiators, light irradiation or both. Radical initiators are known toone skilled in the art. They include, for example,azo-bis-isobutyronitrile (AIBN) and benzoyl peroxide (BPO).

The compound of formula (I) is prepared, e.g., by dissolving anarylisothiocyanate of formula (C), a bromomethyl heteroaryl of formula(E) (1 equivalent) and the cyanamide (F) (2 equivalents) int-butanol/acetonitrile. The resulting reaction mixture is then stirredat ambient temperature for a period of time of between about 2 hours andabout 6 hours, preferably for about 3 hours. The compound of formula (I)is then isolated from the reaction mixture by standard isolationtechniques, such as extraction and concentration, and purification bychromatography.

All compounds of the invention which exist in base or acid form can beconverted to their pharmaceutically acceptable salts by treatment withthe appropriate inorganic or organic base or acid by methods known toone of ordinary skill in the art. Salts of the compounds of theinvention can be converted to their free base or acid form by standardtechniques known to one skilled in the art.

The following specific Synthetic Preparations (for starting materialsand intermediates) and Synthetic Examples (for compounds of formula (I))are provided as a guide to assist in the practice of the invention, andare not intended as a limitation on the scope of the invention. Thenumber following each compound below refers to its number in Table 1, asdiscussed in more detail below.

Synthetic Preparation 1 1-(2-(4-Isothiocyanatophenoxy)ethyl)pyrrolidine

2-(1-Pyrrolidinoethoxy)aniline (2.5 g, 12.2 mMol) and1,1′-thiocarbonyldi-2(1H)-pyridone (2.83 g, 12.2 mMol) were stirred atroom temperature in dichloromethane (30 mL) for 4 hours. The reactionmixture was washed twice with water and once with saturated aqueoussodium chloride solution. The organic layer was dried over anhydroussodium sulfate and concentrated under vacuum, to give1-(2-(4-isothiocyanatophenoxy)ethyl)pyrrolidine (C-1) as a reddishsyrup, 2.88 g. ¹H NMR (CDCl₃, 300 MHz) 7.13 (d, 2H), 6.85 (d, 2H), 4.08(t, 2H), 2.89 (t, 2H), 2.61 (m, 4H), 1.81 (m, 4H) ppm; MS (ES) 249(M⁺H).

Synthetic Preparation 2 Synthesis of 4-Methyl-6,7-dimethoxyquinazoline

2-Amino-4,5-dimethoxyacetophenone (5.0 g) and boron trifluoride etherate(1.5 mL) were heated in formamide (80 mL) at 140° C. for 18 h. Thereaction mixture was cooled to room temperature and extracted threetimes with benzene. The combined organic layers were dried overanhydrous sodium sulfate and concentrated under vacuum. Flashchromatography on silical gel, eluting with a mixture of 98/2dichloromethane/methanol gave 4-methyl-6,7-dimethoxyquinazoline (D-1) asa yellow solid, 3.43 g; ¹H NMR (CDCl₃, 300 MHz) 8.99 (s, 1H), 7.30 (s,1H), 7.18 (s, 1H), 4.05 (s, 6H), 2.87 (s, 1H) ppm; MS (ES) 205 (M⁺H).

Synthetic Preparation 3 4-(Bromomethyl)-6,7-dimethoxyquinazoline

4-Methyl-6,7-dimethoxyquinazoline (D-1) (3.43 g, 14.7 mMol),N-bromosuccinimide (NBS) (2.64 g, 14.7 mMol) and benzoyl peroxide (BPO)(500 mg) were heated under reflux in 200 mL of carbon tetrachloride withirradiation by a 200 W sun lamp for 5 h. The reaction mixture was cooledto room temperature, diluted with dichloromethane and extracted twicewith water. The combined organic layers were dried over anhydrous sodiumsulfate and concentrated under vacuum. Flash chromatography on silicagel, eluting with hexanes/ethyl acetate gave4-bromomethyl-6,7-dimethoxyquinazoline (E-1) as a pinkish solid, 1.39 g;¹H NMR (CDCl₃, 300 MHz) 9.07 (s, 1H), 7.34 (s, 1H), 7.30 (s, 1H), 4.85(s, 2H), 4.06 (s, 6H) ppm; ¹³C NMR (CDCl₃, 75 MHz) 161.22, 156.32,153.45, 150.72, 149.22, 118.85, 107.47, 101.78, 56.84, 56.70, 30.13; MS(ES) 283/285 (M⁺H).

Synthetic Example 1 Preparation of5-(6,7-Dimethoxyquinazolin-4-yl)-N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine

4-(Bromomethyl)-6,7-dimethoxyquinazoline (E-1) (291 mg),1-(2-(4-isothiocyanatophenoxy)ethyl)pyrrolidine (C-1) (330 mg, 1 eq) andcyanamide (100 mg, 2 eq) were dissolved in 1/1 anhydroust-butanol/acetonitrile (8 mL). The reaction was stirred for 3 h at roomtemperature, then quenched with brine. The reaction was extracted with amixture of ethyl acetate and methanol. The organic layer was dried overanhydrous sodium sulfate, concentrated under vacuum and dried overnightunder vacuum. The residue was taken up in anhydrous tetrahydrofuran (10mL) and cooled to −70° C. under nitrogen. Then 2.5 mL of a 1.6 Msolution of n-butyllithium in hexanes was added. After 0.5 h at −70° C.the cooling bath was removed. After a total of 4 h the reaction wasquenched with water, extracted with a mixture of ethyl acetate andmethanol, dried over anhydrous sodium sulfate and concentrated undervacuum. The highly polar product was purified by radial chromatography(chromatotron) eluting with 95% dichloromethane and 5% 2M ammonia inmethanol to yield5-(6,7-dimethoxyquinazolin-4-yl)-N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine,compound #1, as a bright orange solid (39 mg); ¹H NMR (DMSO-d₆, 300 MHz)8.60 (s, 1H), 8.46 (brs, 2H), 7.58 (m, 3H), 7.15 (s, 1H), 6.93 (d, 2H),4.05 (t, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 2.83 (t, 2H), 2.50 (m, 4H),1.70 (m, 4H) ppm; MS (ES) 493.17 (M⁺H).

Synthetic Example 2

In a similar manner as described above in Synthetic Example 1, thefollowing compounds of formula (I) were made with the appropriatelysubstituted starting materials. The number following each compound belowrefers to its number in Table 1, as discussed in more detail below.

-   N²-(4-methoxyphenyl)-5-(pyridin-2-yl)thiazole-2,4-diamine, compound    #2, MS (ES) 298.97 (M⁺H);-   5-(quinoxalin-2-yl)-N²-(3,4,5-trimethoxyphenyl)thiazole-2,4-diamine,    compound #3, ¹H NMR (CDCl₃, 300 MHz) 8.22 (s, 1H), 7.63 (m, 2H),    7.43 (t, 1H), 7.26 (m, 1H), 6.64 (s, 2H), 3.71 (s, 6H), 3.64 (s, 3H)    ppm; MS (ES) 410.12 (M⁺H);-   N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(quinoxalin-2-yl)thiazole-2,4-diamine,    compound #4, ¹H NMR (CDCl₃, 300 MHz) 8.17 (s, 1H), 7.57 (m, 2H),    7.36 (t, 1H), 7.22 (m, 3H), 6.71 (d, 2H), 4.27 (m, 2H), 3.29 (m,    2H), 3.16 (m, 4H), 1.87 (m, 4H) ppm; MS (ES) 433.16 (M⁺H);-   N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(quinazolin-4-yl)thiazole-2,4-diamine,    compound #5, ¹H NMR (CDCl₃/MeOD₄, 300 MHz) 8.57 (s, 1H), 8.07 (d,    1H), 7.55 (m, 2H), 7.30 (m, 3H), 6.83 (d, 2H), 4.01 (t, 2H), 2.83    (t, 2H), 2.57 (m, 4H), 1.74 (m, 4H) ppm; ¹³C NMR (75 MHz) 169.10,    163.99, 159.96, 156.19, 152.65, 149.48, 132.51, 132.37, 127.42,    126.02, 125.66, 123.04, 120.54, 115.39, 89.53, 67.09, 55.16, 54.85,    23.61; MS (ES) 432.91 (M⁺H);-   5-(quinazolin-4-yl)-N²-(3,4,5-trimethoxyphenyl)thiazole-2,4-diamine,    compound #6, ¹H NMR (DMSO-d₆, 300 MHz) 8.81 (br s, 2H), 8.70 (s,    1H), 8.20 (d, 1H), 8.12 (s, 1H), 7.75 (m, 2H), 7.58 (t, 1H), 7.03    (s, 2H), 3.80 (s, 6H), 3.64 (s, 3H) ppm; MS (ES) 410.04 (M⁺H);-   5-(isoquinolin-1-yl)-N²-(4-morpholinophenyl)thiazole-2,4-diamine,    compound #7, ¹H NMR (CDCl₃, 300 MHz) 8.43 (d, 1H), 8.32 (d, 1H),    7.81 (m, 1H), 7.67 (m, 1H), 7.57 (m, 1H), 7.31 (d, 2H), 7.11 (d,    1H), 6.94 (d, 2H), 3.88 (m, 4H), 3.17 (m, 4H) ppm; MS (ES) 404.10    (M⁺H);

5-(isoquinolin-1-yl)-N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine,compound #8, ¹H NMR (CDCl₃/MeOD₄, 300 MHz) 8.26 (d, 1H), 8.14 (d, 1H),7.59 (d, 1H), 7.40 (t, 1H), 7.38 (t, 1H), 7.26 (d, 2H), 7.12 (d, 1H),6.77 (d, 2H), (4.20, m, 2H, obscured by solvent), 3.37 (m, 2H), 3.26 (m,4H), 1.96 (m, 4H) ppm; MS (ES) 432.08 (M⁺H);

-   5-(benzo[d]thiazol-2-yl)-N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine,    compound #9, ¹H NMR (CDCl₃, 300 MHz) 8.24 (s, 1H), 7.56 (t, 1H),    7.20-7.30 (m, 4H), 7.00 (t, 1H), 6.77 (d, 2H), 4.11 (t, 2H), 3.19    (m, 4H), 3.03 (m, 4H), 1.87 (m, 4H) ppm; MS (ES) 438.04 (M⁺H);-   5-(6,7-dimethoxyquinazolin-4-yl)-N²-(4-morpholinophenyl)thiazole-2,4-diamine,    compound #10, ¹H NMR (DMSO-d₆, 300 MHz) 10.53 (s, 1H), 8.60 (s, 1H),    8.48 (brs, 2H), 7.58 (m, 3H), 7.15 (s, 1H), 6.93 (d, 2H), 3.93 (s,    3H), 3.92 (s, 3H), 3.72 (m, 4H), 3.05 (m, 4H) ppm; MS (ES) 465.17    (M⁺H);-   5-(6,7-dimethoxyquinazolin-4-yl)-N²-(4-(4-methyl    piperazin-1-yl)phenyl)thiazole-2,4-diamine, compound #11, ¹H NMR    (CDCl₃/MeOD₄, 300 MHz) 8.10 (s, 1H), 8.03 (s, 3H), 7.24 (m, 3H),    6.78 (s, 1H), 6.69 (d, 2H), 3.72 (s, 3H), 3.71 (s, 3H), 3.05 (m,    4H), 2.75 (m, 4H), 2.37 (s, 3H) ppm; MS (ES) 478.15 (M⁺H); and-   N²-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-5-(thieno[3,2-d]pyrimidin-4-yl)thiazole-2,4-diamine,    compound #12, ¹H NMR (CDCl₃/MeOD₄, 300 MHz) 8.62 (s, 1H), 8.02 (brs,    2H), 8.75 (d, 1H), 7.30 (m, 3H), 6.95 (d, 2H), 3.22 (m, 4H),    2.55-2.80 (m, 4H), 2.45 (m, 1H), 32.36 (m, 1H), 2.20 (m, 1H), 1.78    (m, 2H), 1.50 (m, 1H), 1.35 (m, 4H), 1.04 (m, 1H) ppm; MS (ES)    504.15 (M⁺H).-   N²-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-5-(6,7-dimethoxyquinazolin-4-yl)thiazole-2,4-diamine,    compound #13, ¹H-NMR (CDCl₃/MeOH-d₄, 300 MHz) 8.24 (s, 1H), 7.34 (d,    2H), 7.23 (s, 1H), 7.01 (s, 1H), 6.78 (d, 2H), 3.98 (s, 6H), 3.26    (m, 4H), 2.85-3.10 (m, 4H), 2.77 (m, 1H), 2.42 (m, 1H), 2.37 (m,    1H), 1.78 (m, 2H), 1.30-1.50 (m, 6H); MS (ES) 558 (M+H).-   N²-(3-chloro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(6,7-dimethoxyquinazolin-4-yl)thiazole-2,4-diamine,    compound #14, ¹H-NMR (CDCl₃/MeOH-d₄, 300 MHz) 8.07 (s, 1H), 7.53 (s,    1H), 7.12 (m, 1H), 7.10 (s, 1H), 6.75 (s, 1H), 6.67 (d, 1H), 4.12    (m, 2H), 3.72 (s, 3H), 3.70 (s, 3H), 3.35 (m, 2H), 3.23 (m, 4H),    1.87 (m, 4H); MS (ES) 527 (M+H)

Biological Example

The compounds of the invention were tested in the following assay fortheir ability to inhibit Axl activity.

Phospho-Akt In-Cell Western Assay

Reagents and Buffers:

-   Cell culture plate: 96 well assay plate (Corning 3610), white, clear    bottom, tissue-culture treated.-   Cells: Hela cells.-   Starvation medium: For Axl stimulation: 0.5% FCS (fetal calf serum)    in DMEM, plus Axl/Fc (extracellular domain of AXL fused to    immunoglobulin Fc region) (R&D, 154-AL) 500 ng/mL.-   For EGF (epidermal growth factor) stimulation: 0.5% FCS in DMEM    (Dulbecco's modified Eagles medium).-   Poly-L-Lysine 0.01% solution (the working solution): 10 μg/ml,    dilute In PBS (phosphate buffered saline).-   Axl antibody cross-linking:    -   1^(st): Mouse anti-Axl (R&D, MAB154).    -   2^(nd): Biotin-SP-conjugated AffiniPure goat anti-mouse IgG        (H+L) (Jackson ImmunoResearch #115-065-003).-   Fixing buffer: 4% formaldehyde in PBS.-   Wash buffer: 0.1% TritonX-100 in PBS.-   Quenching buffer: 3% H₂O₂, 0.1% Azide in wash buffer, Azide and    hydrogen peroxide (H₂O₂) are added fresh.-   Blocking buffer: 5% BSA in TBST (tris buffered saline plus 0.1%    Tween 20).-   Primary antibody: Rabbit anti-human Phospho-Akt antibody (Cell    Signaling 9271): 1×250 diluted in blocking buffer.-   Secondary antibody: HRP (horse radish peroxidase)-conjugated Goat    anti-Rabbit secondary, stock solution: Jackson ImmunoResearch (Goat    anti-Rabbit HRP, #111-035-144) 1:1 diluted in glycerol, store at    −20° C. The working solution: 1×2000 dilution of stock in blocking    buffer.-   Chemiluminescent working solution (Pierce, 37030): SuperSignal ELISA    (enzyme linked immunosorbant assay) Pico Chemiluminescent substrate.-   Crystal Violet solution: Stock: 2.5% Crystal violet in methanol,    filtered and kept at ambient temperature. The working solution:    dilute the stock 1:20 with PBS immediately before use.-   10% SDS: working solution: 5% SDS (sodium dodecylsulfate), diluted    in PBS    Methods:    Day 1:

A 96 well TC (tissue culture treated) plate was coated with 10 μg/mLpoly-L-Lysine at 37° C. for 30 min, washed twice with PBS, and air-driedfor 5 minutes before cells were added. Hela cells were seeded at 10,000cells/well and the cells were starved in 100 μL starvation mediumcontaining Axl/Fc for 24 hrs.

Day 2:

The cells were pre-treated with test compounds by adding 100 μL of 2×test compound to the starvation medium on the cells. The cells wereincubated at 37° C. for 1 hr before stimulation.

The cells were stimulated by Axl-antibody cross-linking as follows: A5×1^(st)/2^(nd) Axl antibody mixture was made (37.5 μg/mL 1^(st)/100μg/mL 2^(nd)) in starvation medium and nutated at 4° C. with thoroughmixing for 1-2 hours for clustering. The resulting mix was warmed to 37°C. 50 μL of 5×Axl 1^(st)/2^(nd) of antibody cluster was added to thecells and the cells were incubated at 37° C. for 5 min.

After 5 minutes stimulation, the plate was flicked to remove medium andthe plate was tapped onto paper towels. Formaldehyde (4.0% in PBS, 100μL) was added to fix the cells and the cells were incubated at ambienttemperature for 20 min without shaking.

The cells were washed with a plate washer buffer to remove theformaldehyde solution. The plate was flicked to removed excess washbuffer and tapped onto paper towels. Quenching buffer (100 μL) was addedto each well and the cells were incubated at ambient temperature for 20minutes without shaking.

The cells were washed with a plate washer buffer to remove the quenchingbuffer. Blocking buffer (100 μL) was added and the cells were incubatedat ambient temperature for at least an hour with gentle shaking.

The cells were washed with a plate washer buffer and diluted primaryantibody (50 μL) was added to each well (blocking buffer was added tothe negative control wells instead). The plates were incubated overnightat 4° C. with gentle shaking.

Day 3:

The wash buffer was removed, diluted secondary antibody (100 μL) wasadded, and the cells were incubated at ambient temperature for 1 hourwith gentle shaking. During the incubation, the chemiluminescent reagentwas brought to ambient temperature.

The secondary antibody was removed by washing the cells 1× with washbuffer, 1× with PBS by plate washer. The PBS was removed from the plateand the chemiluminescent reagent (80 μL: 40 μL A and 40 μL B) was addedto each well at ambient temperature.

The resulting chemiluminescence was read with a Luminomitor within 10minutes to minimize changes in signal intensity. After reading thechemiluminescence, the cells were washed 1× with wash buffer and 1× withPBS by plate washer. The plate was tapped onto paper towels to removeexcess liquid from wells and air-dried at ambient temperature for 5minutes.

Crystal Violet working solution (60 μL) was added to each well and thecells were incubated at ambient temperature for 30 min. The crystalviolet solution was removed, and the wells were rinsed with PBS, thenwashed 3× with PBS (200 μL) for 5 minutes each.

5% SDS solution (70 μL) was added to each well and the cells wereincubated on a shaker for 30 min at ambient temperature.

The absorbance was read at 590 nM on a Wallac photospec. The 590 nMreadings indicated the relative cell number in each well. This relativecell number was then used to normalize each luminescence reading.

The results of the ability of the compounds of the invention to inhibitAxl activity, when tested in the above assay, are shown in the followingTable 1 wherein the level of activity (i.e., the IC₅₀) for each compoundis indicated in Table 1. The compound numbers in the Table referred tothe compounds disclosed herein as being prepared by the methodsdisclosed herein:

TABLE 1

Cpd # Compound Name R¹ R² R³ R⁴ R⁵ IC₅₀* 1 5-(6,7-Dimethoxyquinazolin-4-yl)-N²-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)thiazole-2,4- diamine H

H H A 2 N²-(4-methoxyphenyl)-5- (pyridin-2-yl)thiazole-2,4- diamine H

H H C 3 5-(quinoxalin-2-yl)-N²-(3,4,5- trimethoxyphenyl)thiazole-2,4-diamine H

H H A 4 N²-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-5-(quinoxalin-2-yl)thiazole-2,4-diamine H

H H A 5 N²-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-5-(quinazolin-4-yl)thiazole-2,4-diamine H

H H A 6 5-(quinazolin-4-yl)-N²-(3,4,5- trimethoxyphenyl)thiazole-2,4-diamine H

H H C 7 5-(isoquinolin-1-yl)-N²-(4- morpholinophenyl)thiazole-2,4-diamine H

H H B 8 5-(isoquinolin-1-yl)-N²-(4-(2- (pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4- diamine H

H H C 9 5-(benzo[d]thiazol-2-yl)-N²-(4-(2- (pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4- diamine H

H H A 10 5-(6,7-dimethoxyquinazolin-4- yl)-N²-(4-morpholinophenyl)thiazole-2,4- diamine H

H H A 11 5-(6,7-dimethoxyquinazolin-4- yl)-N²-(4-(4-methylpiperazin-1-yl)phenyl)thiazole-2,4-diamine H

H H A 12 N²-(4-(4-(bicyclo[2.2.1]heptan-2- yl)piperazin-1-yl)phenyl)-5-(thieno[3,2-d]pyrimidin-4- yl)thiazole-2,4-diamine H

H H A 13 N²-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-5-(6,7- dimethoxyquinazolin-4-yl)thiazole-2,4-diamine H

H H C 14 N²-(3-chloro-4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-5-(6,7-dimethoxyquinazolin-4- yl)thiazole-2,4-diamine H

H H A IC₅₀ activity: A = 1 μM to 10 μM B = >10 to 20 μM C = >20 μM

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification and/or listedin the Application Data Sheet are incorporated herein by reference, intheir entireties.

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

1. A compound of formula (I):

wherein: R¹, R⁴ and R⁵ are each independently hydrogen, alkyl, aryl,aralkyl, —C(O)R¹⁰, or —C(O)N(R⁶)R⁷; R² is aryl or heteroaryl, the arylor heteroaryl being optionally substituted with one or more substituentsselected from the group consisting of cyano, nitro, halo, haloalkyl,alkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, —R¹⁰—R⁹, —R¹⁰—O—R¹¹—OR⁹,—R¹⁰—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,—R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2),—R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,—R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,—R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); R³ isheteroaryl having at least six ring atoms, the heteroaryl beingoptionally substituted with one or more substituents selected from thegroup consisting of cyano, nitro, halo, haloalkyl, alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—OR⁹,—R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹, —R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷,—R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2), —R¹⁰—O—R¹¹—N(R⁶)R⁷,—R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹, —R¹⁰—N(R⁶)R⁷,—R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹,—R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1 or 2), —R¹⁰—S(O)_(t)OR⁹, (where t is1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is 0, 1 or 2), and—R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); each R⁶ and R⁷ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted aralkenyl, optionally substituted aralkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted cycloalkylalkenyl, optionally substitutedcycloalkylalkynyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R¹¹—OR⁹, —R¹¹—CN, —R¹¹—NO₂, —R¹¹—N(R⁹)₂,—R¹¹C(O)OR⁹ and —R¹¹—C(O)N(R⁹)₂; each R⁹ is independently selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,haloalkenyl, haloalkynyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl,optionally substituted cycloalkylalkynyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heterocyclylalkenyl, optionally substitutedheterocyclylalkynyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyl,and optionally substituted heteroarylalkynyl; each R¹⁰ is independentlyselected from the group consisting of a direct bond, an optionallysubstituted straight or branched alkylene chain, an optionallysubstituted straight or branched alkenylene chain and an optionallysubstituted straight or branched alkynylene chain; each R¹¹ isindependently selected from the group consisting of an optionallysubstituted straight or branched alkylene chain, an optionallysubstituted straight or branched alkenylene chain and an optionallysubstituted straight or branched alkynylene chain; and each R¹² ishydrogen, alkyl, cyano, nitro or —OR⁹; with the proviso that thecompound is notN²-(1,4-benzodioxan-6yl)-5-(pyridin-2-yl)thiazole-2,4-diamine, and whenR² is phenyl, 4-chlorophenyl or methoxy-substituted phenyl, R³ is notquinolin-2yl, pyridinyl or substituted pyridinyl, as an isolatedstereoisomer or mixture thereof, or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1 wherein: R¹, R⁴ and R⁵ are eachhydrogen, R² is aryl or heteroaryl, the aryl or heteroaryl beingoptionally substituted with one or more substituents selected from thegroup consisting of cyano, nitro, halo, haloalkyl, alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,—R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2),—R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,—R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,—R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); R³ isheteroaryl having at least six ring atoms, the heteroaryl beingoptionally substituted with one or more substituents selected from thegroup consisting of cyano, nitro, halo, haloalkyl, alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,—R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,—R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹S(O)_(p)R⁹ (where p is 0, 1 or 2),—R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,—R¹⁰—N(R⁶)R⁷), —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,—R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); each R⁶ and R⁷are each independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,hydroxyalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R¹¹—OR⁹, —R¹¹—CN, —R¹¹—NO₂, —R¹¹—N(R⁹)₂,—R¹¹—C(O)OR⁹ and —R¹¹—C(O)N(R⁹)₂; each R⁹ is independently selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,haloalkenyl, haloalkynyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl,optionally substituted cycloalkylalkynyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heterocyclylalkenyl, optionally substitutedheterocyclylalkynyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyl,and optionally substituted heteroarylalkynyl; each R¹⁰ is independentlyselected from the group consisting of a direct bond, an optionallysubstituted straight or branched alkylene chain, an optionallysubstituted straight or branched alkenylene chain and an optionallysubstituted straight or branched alkynylene chain; each R¹¹ isindependently selected from the group consisting of an optionallysubstituted straight or branched alkylene chain, an optionallysubstituted straight or branched alkenylene chain and an optionallysubstituted straight or branched alkynylene chain; and each R¹² ishydrogen, alkyl, cyano, nitro or —OR⁹.
 3. The compound of claim 2wherein: R¹, R⁴ and R⁵ are each hydrogen, R² is aryl optionallysubstituted with one or more substituents selected from the groupconsisting of cyano, nitro, halo, haloalkyl, alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—OR⁹,—R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹, —R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷,—R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2), —R¹⁰—O—R¹¹—N(R⁶)R⁷,—R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹, —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹,—R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷, —R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹,—R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1 or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1or 2), —R¹⁰—S(O)_(p)R⁹ (where p is 0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷(where t is 1 or 2); R³ is heteroaryl having at least six ring atoms,the heteroaryl being optionally substituted with one or moresubstituents selected from the group consisting of cyano, nitro, halo,haloalkyl, alkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, —R¹⁰—OR⁹,—R¹⁰—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,—R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2),—R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,—R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,—R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); and each R⁶and R⁷ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,hydroxyalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R¹¹—OR⁹, —R¹¹—CN, —R¹¹—NO₂, —R¹¹—N(R⁹)₂,—R¹¹—C(O)OR⁹ and —R¹¹—C(O)N(R⁹)₂; each R⁹ is independently selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,haloalkenyl, haloalkynyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl,optionally substituted cycloalkylalkynyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heterocyclylalkenyl, optionally substitutedheterocyclylalkynyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyl,and optionally substituted heteroarylalkynyl; each R¹⁰ is independentlyselected from the group consisting of a direct bond, an optionallysubstituted straight or branched alkylene chain, an optionallysubstituted straight or branched alkenylene chain and an optionallysubstituted straight or branched alkynylene chain; each R¹¹ isindependently selected from the group consisting of an optionallysubstituted straight or branched alkylene chain, an optionallysubstituted straight or branched alkenylene chain and an optionallysubstituted straight or branched alkynylene chain; and each R¹² ishydrogen, alkyl, cyano, nitro or —OR⁹.
 4. The compound of claim 3wherein: R¹, R⁴ and R⁵ are each hydrogen, R² is phenyl optionallysubstituted with one or more substituents selected from the groupconsisting of cyano, nitro, halo, haloalkyl, alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, —R¹⁰—OR⁹, R¹⁰—O—R¹¹—OR⁹,—R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,—R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2),—R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,—R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,—R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); R³ isheteroaryl selected from the group consisting of pyridinyl,pyrazolo[3,4-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl,pyrido[3,4-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, quinazolinyl, quinoxalinyl, quinolinyl,isoquinolinyl and benzo[d]thiazolyl, the heteroaryl being optionallysubstituted with one or more substituents selected from the groupconsisting of alkyl and —R¹⁰—OR⁹; each R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,—R¹¹—OR⁹, —R¹¹—CN, —R¹¹—NO₂, —R¹¹—N(R⁹)₂, —R¹¹—C(O)OR⁹ and—R¹¹—C(O)N(R⁹)₂; each R⁹ is independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,haloalkynyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, andoptionally substituted heteroarylalkynyl; each R¹⁰ is independentlyselected from the group consisting of a direct bond, an optionallysubstituted straight or branched alkylene chain, an optionallysubstituted straight or branched alkenylene chain and an optionallysubstituted straight or branched alkynylene chain; each R¹¹ isindependently selected from the group consisting of an optionallysubstituted straight or branched alkylene chain, an optionallysubstituted straight or branched alkenylene chain and an optionallysubstituted straight or branched alkynylene chain; and each R¹² ishydrogen, alkyl, cyano, nitro or —OR⁹.
 5. The compound of claim 4,wherein: R¹, R⁴ and R⁵ are each hydrogen, R² is phenyl substituted withone or more —OR⁹; and each R⁹ is independently selected from the groupconsisting of alkyl and optionally substituted heterocyclylalkyl.
 6. Thecompound of claim 5 selected from the group consisting of:5-(quinoxalin-2-yl)-N²-(3,4,5-trimethoxyphenyl)thiazole-2,4-diamine;N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(quinoxalin-2-yl)thiazole-2,4-diamine;N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(quinazolin-4-yl)thiazole-2,4-diamine;5-(quinazolin-4-yl)-N²-(3,4,5-trimethoxyphenyl)thiazole-2,4-diamine;5-(isoquinolin-1-yl)-N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine;5-(benzo[d]thiazol-2-yl)-N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine;5-(6,7-dimethoxyquinazolin-4-yl)-N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine;andN²-(3-chloro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(6,7-dimethoxyquinazolin-4-yl)thiazole-2,4-diamine.7. The compound of claim 4 wherein: R¹, R⁴ and R⁵ are each hydrogen; R²is phenyl substituted with one or more optionally substitutedheterocyclyl; and R³ is heteroaryl selected from the group consisting ofpyridinyl, pyrazolo[3,4-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl,pyrido[3,4-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, quinazolinyl, quinoxalinyl, quinolinyl,isoquinolinyl and benzo[d]thiazolyl, the heteroaryl being optionallysubstituted with one or more substituents selected from the groupconsisting of alkyl and —OR⁹; and each R⁹ is independently alkyl.
 8. Thecompound of claim 7 wherein: R² is phenyl substituted with one or moreN-heterocyclyl, the N-heterocyclyl being optionally substituted with oneor more substituents selected from the group consisting of alkyl,cycloalkyl and —C(O)R⁹; and each R⁹ is independently alkyl.
 9. Thecompound of claim 8 selected from the group consisting of:5-(isoquinolin-1-yl)-N²-(4-morpholinophenyl)thiazole-2,4-diamine;5-(6,7-dimethoxyquinazolin-4-yl)-N²-(4-morpholinophenyl)thiazole-2,4-diamine;5-(6,7-dimethoxyquinazolin-4-yl)-N²-(4-(4-methylpiperazin-1-yl)phenyl)thiazole-2,4-diamine;N²-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-5-(thieno[3,2-d]pyrimidin-4-yl)thiazole-2,4-diamine;andN²-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-5-(6,7-dimethoxyquinazolin-4-yl)thiazole-2,4-diamine.10. The compound of claim 4 wherein: R¹, R⁴ and R⁵ are each hydrogen; R²is phenyl substituted with one or more substituents selected from thegroup consisting of optionally substituted heterocyclylalkyl, halo, —OR⁹and —C(O)R⁹; and R³ is heteroaryl selected from the group consisting ofpyridinyl, pyrazolo[3,4-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl,pyrido[3,4-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, quinazolinyl, quinoxalinyl, quinolinyl,isoquinolinyl and benzo[d]thiazolyl, the heteroaryl being optionallysubstituted with one or more substituents selected from the groupconsisting of alkyl and —OR⁹; and each R⁹ is independently selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,haloalkenyl, haloalkynyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl,optionally substituted cycloalkylalkynyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heterocyclylalkenyl, optionally substitutedheterocyclylalkynyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyl,and optionally substituted heteroarylalkynyl.
 11. The compound of claim1, wherein: R¹, R⁴ and R⁵ are each hydrogen, R² is heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of cyano, nitro, halo, haloalkyl, alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN,—R¹⁰—O—R¹¹—C(O)OR⁹, —R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹S(O)_(p)R⁹ (wherep is 0, 1 or 2), —R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H,—R¹⁰—OC(O)—R⁹, —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); R³ isheteroaryl having at least six ring atoms, the heteroaryl beingoptionally substituted with one or more substituents selected from thegroup consisting of cyano, nitro, halo, haloalkyl, alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, R¹⁰—O—R¹¹—C(O)OR⁹,—R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹, (where p is 0, 1 or 2),—R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,—R¹⁰—(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,—R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹, (where t is1 or 2), —R¹⁰—S(O)_(t)R⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where pis 0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); each R⁶ andR⁷ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,hydroxyalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R¹¹—OR⁹, —R¹¹—CN, —R¹¹—NO₂, —NO₂,—R¹¹—N(R⁹)₂, —R¹¹—C(O)OR⁹ and —R¹¹—C(O)N(R⁹)₂; each R⁹ is independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedcycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heterocyclylalkenyl, optionally substitutedheterocyclylalkynyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyl,and optionally substituted heteroarylalkynyl; each R¹⁰ is independentlyselected from the group consisting of a direct bond, an optionallysubstituted straight or branched alkylene chain, an optionallysubstituted straight or branched alkenylene chain and an optionallysubstituted straight or branched alkynylene chain; each R¹¹ isindependently selected from the group consisting of an optionallysubstituted straight or branched alkylene chain, an optionallysubstituted straight or branched alkenylene chain and an optionallysubstituted straight or branched alkynylene chain; and each R¹² ishydrogen, alkyl, cyano, nitro or —OR⁹; as isolated stereoisomers ormixtures thereof, as tautomers or mixtures thereof, or aspharmaceutically acceptable salts, or N-oxides thereof.
 12. The compoundof claim 1 wherein: R¹, R⁴ and R⁵ are each independently hydrogen,alkyl, aryl, aralkyl, —C(O)R¹⁰, or —C(O)N(R⁶)R⁷; R² is aryl orheteroaryl, the aryl or heteroaryl being optionally substituted with oneor more substituents selected from the group consisting of cyano, nitro,halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, —R¹⁰—OR⁹,—R¹⁰—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—O—R¹¹—OR⁹, R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,—R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2),—R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,—R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,—R¹⁰N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); R³ ispolycyclic heteroaryl optionally substituted with one or moresubstituents selected from the group consisting of cyano, nitro, halo,haloalkyl, alkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, —R¹⁰—OR⁹,R¹⁰—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN—R¹⁰—O—R¹¹—C(O)OR⁹,—R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2),—R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,—R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,—R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); each R⁶ and R⁷are each independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,hydroxyalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R¹¹—OR⁹, —R¹¹—CN, —R¹¹—NO₂, —R¹¹—N(R⁹)₂,—R¹¹—C(O)OR⁹ and —R¹¹—C(O)N(R⁹)₂; each R⁹ is independently selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,haloalkenyl, haloalkynyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl,optionally substituted cycloalkylalkynyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heterocyclylalkenyl, optionally substitutedheterocyclylalkynyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyland optionally substituted heteroarylalkynyl; each R¹⁰ is independentlyselected from the group consisting of a direct bond, an optionallysubstituted straight or branched alkylene chain, an optionallysubstituted straight or branched alkenylene chain and an optionallysubstituted straight or branched alkynylene chain; each R¹¹ isindependently selected from the group consisting of an optionallysubstituted straight or branched alkylene chain, an optionallysubstituted straight or branched alkenylene chain and an optionallysubstituted straight or branched alkynylene chain; and each R¹² ishydrogen, alkyl, cyano, nitro or —OR⁹; as isolated stereoisomers ormixtures thereof, as tautomers or mixtures thereof, or aspharmaceutically acceptable salts, or N-oxides thereof.
 13. The compoundof claim 12, represented by formula (Ia):

wherein: X is N or CH; w is 0, 1, 2, 3, 4, 5, 6, 7 or 8; R¹, R^(3a), R⁴and R⁵ are each independently hydrogen, alkyl, aryl, aralkyl, —C(O)R¹⁰,or —C(O)N(R⁶)R⁷; R² is aryl or heteroaryl optionally substituted withone or more substituents selected from the group consisting of cyano,nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,—R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN,—R¹⁰—O—R¹¹—C(O)OR⁹, —R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (wherep is 0, 1 or 2), —R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H,—R¹⁰—OC(O)—R⁹, —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹,—R¹⁰—C(O)N(R⁶)R⁷, —R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹,—R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1 or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1or 2), —R¹⁰—S(O)_(p)R⁹ (where p is 0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷(where t is 1 or 2); A is cycloalkyl, heterocyclyl, heteroaryl or aryl;each R^(3b) is independently selected from the group consisting ofcyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,—R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹, —R¹¹—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN,—R¹⁰—O—R¹¹—C(O)OR⁹, —R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (wherep is 0, 1 or 2), —R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H,—R¹⁰—OC(O)—R⁹, —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹,—R¹⁰—C(O)N(R⁶)R⁷, —R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹,—R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1 or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1or 2), —R¹⁰—S(O)_(p)R⁹ (where p is 0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷(where t is 1 or 2); each R⁶ and R⁷ are each independently selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedcycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heterocyclylalkenyl, optionally substitutedheterocyclylalkynyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyl,optionally substituted heteroarylalkynyl, —R¹¹—OR⁹, —R¹¹—CN, —R¹¹—NO₂,—R¹¹—N(R⁹)₂, —R¹¹—C(O)OR⁹ and —R¹¹—C(O)N(R⁹)₂; each R⁹ is independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedcycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heterocyclylalkenyl, optionally substitutedheterocyclylalkynyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyland optionally substituted heteroarylalkynyl; each R¹⁰ is independentlyselected from the group consisting of a direct bond, an optionallysubstituted straight or branched alkylene chain, an optionallysubstituted straight or branched alkenylene chain and an optionallysubstituted straight or branched alkynylene chain; each R¹¹ isindependently selected from the group consisting of an optionallysubstituted straight or branched alkylene chain, an optionallysubstituted straight or branched alkenylene chain and an optionallysubstituted straight or branched alkynylene chain; and each R¹² ishydrogen, alkyl, cyano, nitro or —OR⁹; as isolated stereoisomers ormixtures thereof, as tautomers or mixtures thereof, or aspharmaceutically acceptable salts, or N-oxides thereof.
 14. The compoundof claim 13 wherein: w is 0, 1, 2, 3 or 4; R¹, R^(3a), R⁴ and R⁵ areeach hydrogen; R² is phenyl optionally substituted with one or moresubstituents selected from the group consisting of cyano, nitro, halo,haloalkyl, alkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, —R¹⁰—OR⁹,—R¹⁰—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,—R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2),—R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹C(NR¹²)N(R¹²)H, R¹⁰—OC(O)—R⁹,—R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,—R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); A is aryl; andeach R^(3b) is independently selected from the group consisting ofcyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,—R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN,—R¹⁰—O—R¹¹—C(O)OR⁹, —R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (wherep is 0, 1 or 2), —R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹C(NR¹²)N(R¹²)H,—R¹⁰—OC(O)—R⁹, —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹,—R¹⁰—C(O)N(R⁶)R⁷, —R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹,—R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1 or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1or 2), —R¹⁰—S(O)_(p)R⁹ (where p is 0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷(where t is 1 or 2).
 15. The compound of claim 14 wherein: X is N; w is0, 1 or 2; R¹, R^(3a), R⁴ and R⁵ are each hydrogen; R² is phenylsubstituted with one or more substituents selected from the groupconsisting of —OR⁹ and N-heterocyclyl optionally substituted with one ormore substituents selected from the group consisting of alkyl,cycloalkyl and —C(O)R⁹; A is phenyl; each R^(3b) is independently —OR⁹;and each R⁹ is independently alkyl or heterocyclylalkyl.
 16. Thecompound of claim 15 selected from the group consisting of:5-(6,7-dimethoxyquinazolin-4-yl)-N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine;N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(quinazolin-4-yl)thiazole-2,4-diamine;5-(quinazolin-4-yl)-N²-(3,4,5-trimethoxyphenyl)thiazole-2,4-diamine;5-(6,7-dimethoxyquinazolin-4-yl)-N²-(4-morpholinophenyl)thiazole-2,4-diamine;5-(6,7-dimethoxyquinazolin-4-yl)-N²-(4-(4-methylpiperazin-1-yl)phenyl)thiazole-2,4-diamine;N²-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-5-(6,7-dimethoxyquinazolin-4-yl)thiazole-2,4-diamine;andN²-(3-chloro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-(6,7-dimethoxyquinazolin-4-yl)thiazole-2,4-diamine.17. The compound of claim 14 wherein X is CH; w is 0; R¹, R^(3a),R^(3b), R⁴ and R⁵ are each hydrogen; R² is phenyl substituted with oneor more substituents selected from the group consisting of —OR⁹ andN-heterocyclyl optionally substituted with one or more substituentsselected from the group consisting of alkyl, cycloalkyl and —C(O)R⁹; Ais phenyl; each R⁹ is independently alkyl or heterocyclylalkyl.
 18. Thecompound of claim 17 selected from the group consisting of:5-(isoquinolin-1-yl)-N²-(4-morpholinophenyl)thiazole-2,4-diamine; and5-(isoquinolin-1-yl)-N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)thiazole-2,4-diamine.19. The compound of claim 13 wherein: w is 0, 1, 2, 3 or 4; R¹, R^(3a),R⁴ and R⁵ are each hydrogen; R² is phenyl optionally substituted withone or more substituents selected from the group consisting of cyano,nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,—R¹⁰—OR⁹, —R^(10—)O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN,—R¹⁰—O—R¹¹—C(O)OR⁹, —R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (wherep is 0, 1 or 2), —R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H,—R¹⁰—OC(O)—R⁹, —R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹,—R¹⁰—C(O)N(R⁶)R⁷, —R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹,—R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1 or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1or 2), —R¹⁰—S(O)_(p)R⁹ (where p is 0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷(where t is 1 or 2); A is heteroaryl; and each R^(3b) is independentlyselected from the group consisting of cyano, nitro, halo, haloalkyl,alkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,—R¹⁰—O—R¹¹—O—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2),—R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,—R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,—R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).
 20. Thecompound of claim 19 wherein: w is 0; R¹, R^(3a), R^(3b), R⁴ and R⁵ areeach hydrogen; R² is phenyl substituted with one or more N-heterocyclyloptionally substituted with one or more substituents selected from thegroup consisting of alkyl, cycloalkyl and —C(O)R⁹; A is thienyl; andeach R⁹ is independently alkyl.
 21. The compound of claim 20, whereinthe compound isN²-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-5-(thieno[3,2-d]pyrimidin-4-yl)thiazole-2,4-diamine.22. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a therapeutically effective amount of acompound of formula (I):

wherein: R¹, R⁴ and R⁵ are each independently hydrogen, alkyl, aryl,aralkyl, —C(O)R¹⁰, or —C(O)N(R⁶)R⁷; R² is aryl or heteroaryl, the arylor heteroaryl being optionally substituted with one or more substituentsselected from the group consisting of cyano, nitro, halo, haloalkyl,alkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,—R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,—R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2),—R¹¹—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,—R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,—R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); R³ isheteroaryl having at least six ring atoms, the heteroaryl beingoptionally substituted with one or more substituents selected from thegroup consisting of cyano, nitro, halo, haloalkyl, alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, —R¹⁰—OR⁹, —R¹⁰—O—R¹¹—OR⁹,—R¹⁰—O—R¹¹—O—R¹¹—OR⁹, —R¹⁰—O—R¹¹—CN, —R¹⁰—O—R¹¹—C(O)OR⁹,—R¹⁰—O—R¹¹—C(O)N(R⁶)R⁷, —R¹⁰—O—R¹¹—S(O)_(p)R⁹ (where p is 0, 1 or 2),—R¹⁰—O—R¹¹—N(R⁶)R⁷, —R¹⁰—O—R¹¹—C(NR¹²)N(R¹²)H, —R¹⁰—OC(O)—R⁹,—R¹⁰—N(R⁶)R⁷, —R¹⁰—C(O)R⁹, —R¹⁰—C(O)OR⁹, —R¹⁰—C(O)N(R⁶)R⁷,—R¹⁰—N(R⁶)C(O)OR¹⁴, —R¹⁰—N(R⁶)C(O)R⁹, —R¹⁰—N(R⁶)S(O)_(t)R⁹ (where t is 1or 2), —R¹⁰—S(O)_(t)OR⁹ (where t is 1 or 2), —R¹⁰—S(O)_(p)R⁹ (where p is0, 1 or 2), and —R¹⁰—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); each R⁶ and R⁷are each independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,hydroxyalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R¹¹—OR⁹, —R¹¹—CN, —R¹¹—NO₂, —R¹¹—N(R⁹)₂,—R¹¹—C(O)OR⁹ and —R¹¹—C(O)N(R⁹)₂; each R⁹ is independently selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,haloalkenyl, haloalkynyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl,optionally substituted cycloalkylalkynyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heterocyclylalkenyl, optionally substitutedheterocyclylalkynyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyland optionally substituted heteroarylalkynyl; each R¹⁰ is independentlyselected from the group consisting of a direct bond, an optionallysubstituted straight or branched alkylene chain, an optionallysubstituted straight or branched alkenylene chain and an optionallysubstituted straight or branched alkynylene chain; each R¹¹ isindependently selected from the group consisting of an optionallysubstituted straight or branched alkylene chain, an optionallysubstituted straight or branched alkenylene chain and an optionallysubstituted straight or branched alkynylene chain; and each R¹² ishydrogen, alkyl, cyano, nitro or —OR⁹; with the proviso that thecompound is notN²-(1,4-benzodioxan-6-yl)-5-(pyridin-2-yl)thiazole-2,4-diamine, and whenR² is phenyl, 4-chlorophenyl or methoxy-substituted phenyl, R³ is notquinolin-2yl, pyridinyl or substituted pyridinyl, as an isolatedstereoisomer or mixture thereof, or a pharmaceutically acceptable saltthereof.